Determination of an optimal dosing schedule for combining Irinophore C™ and temozolomide in an orthotopic model of glioblastoma.

Our laboratory reported that Irinophore C™ (IrC™; a lipid-based nanoparticulate formulation of irinotecan) is effective against an orthotopic model of glioblastoma (GBM) and that treatment with IrC™ was associated with vascular normalization within the tumor. Here, the therapeutic effects of IrC™ when used in combination with temozolomide (TMZ) in concurrent and sequential treatment schedules were tested. It was anticipated that IrC™ engendered vascular normalization would increase the delivery of TMZ to the tumor and that this would be reflected by improved treatment outcomes. The approach compared equally efficacious doses of irinotecan (IRN; 50 mg/kg) and IrC™ (25 mg/kg) in order to determine if there was a unique advantage achieved when combining TMZ with IrC™. The TMZ sensitive U251MG(O) cell line (null expression of O-6-methylguanine-DNA methyltransferase (MGMT)) modified to express the fluorescent protein mKate2 was inoculated orthotopically into NOD.CB17-SCID mice and treatment was initiated 14 days later. Our results demonstrated that IrC™ and TMZ administered concurrently resulted in optimal treatment outcomes, with 50% long term survivors (>180 days) in comparison to 17% long term survivors in animals treated with IRN and TMZ or TMZ alone. Indeed, the different treatments resulted in a 353%, 222% and 280% increase in median survival time (MST) compared to untreated animals for, respectively, IrC™ combined with TMZ, IRN combined with TMZ, and TMZ alone. When TMZ was administered after completion of IRN or IrC™ dosing, an increase in median survival time of 167-174% was observed compared to untreated animals and of 67% and 74%, respectively, when IRN (50 mg/kg) and IrC™ (25mg/kg) were given as single agents. We confirmed in these studies that after completion of the Q7D×3 dosing of IrC™, but not IRN, the tumor-associated vascular was normalized as compared to untreated tumors. Specifically, reductions in the fraction of collagen IV-free CD31 staining (p<0.05) and reductions in tumor vessel diameter were observed in tumors from IrC™-treated animals when compared to tumors from untreated or IRN treated animals. Analysis by transmission electron microscopy of the ultra-structure of tumors from IrC™-treated and untreated animals revealed that tumor-associated vessels from treated animals were smaller, more organized and exhibited a morphology comparable to normal blood vessels. In conclusion, optimal treatment outcomes were achieved when IrC™ and TMZ were administered concurrently, whereas IrC™ followed by TMZ treatment given sequentially did not confer any therapeutic advantage.

Comparison of success rates, learning curves, and inter-subject performance variability of robot-assisted and manual ultrasound-guided nerve block needle guidance in simulation.

BACKGROUND: This study focuses on a recently developed robotic nerve block system and its impact on learning regional anaesthesia skills. We compared success rates, learning curves, performance times, and inter-subject performance variability of robot-assisted vs manual ultrasound (US)-guided nerve block needle guidance. The hypothesis of this study is that robot assistance will result in faster skill acquisition than manual needle guidance. METHODS: Five co-authors with different experience with nerve blocks and the robotic system performed both manual and robot-assisted, US-guided nerve blocks on two different nerves of a nerve phantom. Ten trials were performed for each of the four procedures. Time taken to move from a shared starting position till the needle was inserted into the target nerve was defined as the performance time. A successful block was defined as the insertion of the needle into the target nerve. Average performance times were compared using analysis of variance. P<0.05 was considered significant. Data presented as mean (standard deviation). RESULTS: All blocks were successful. There were significant differences in performance times between co-authors to perform the manual blocks, either superficial (P=0.001) or profound (P=0.0001); no statistical difference between co-authors was noted for the robot-assisted blocks. Linear regression indicated that the average decrease in time between consecutive trials for robot-assisted blocks of 1.8 (1.6) s was significantly (P=0.007) greater than the decrease for manual blocks of 0.3 (0.3) s. CONCLUSIONS: Robot assistance of nerve blocks allows for faster learning of needle guidance over manual positioning and reduces inter-subject performance variability.

Transcontinental anaesthesia: a pilot study.

BACKGROUND: Although telemedicine is one of the key initiatives of the World Health Organization, no study has explored the feasibility and efficacy of teleanaesthesia. This bi-centre pilot study investigates the feasibility of transcontinental anaesthesia. METHODS: Twenty patients aged ≥ 18 yr undergoing elective thyroid surgery for ≥ 30 min were enrolled in this study. The remote and local set-up was composed of a master-computer (Montreal) and a slave-computer (Pisa). Standard Internet connection, remote desktop control, and video conference software were used. All patients received total i.v. anaesthesia controlled remotely (Montreal). The main outcomes were feasibility, clinical performance, and controller performance of transcontinental anaesthesia. The clinical performance of hypnosis control was the efficacy to maintain bispectral index (BIS) at 45: 'excellent', 'good', 'poor', and 'inadequate' control represented BIS values within 10, from 11 to 20, from 21 to 30, or >30% from target. The clinical performance of analgesia was the efficacy to maintain Analgoscore values at 0 (-9 to 9); -3 to +3 representing 'excellent' pain control, -3 to -6 and +3 to +6 representing 'good' pain control, and -6 to -9 and +6 to +9 representing 'insufficient' pain control. The controller performance was evaluated using Varvel parameters. RESULTS: Transcontinental anaesthesia was successful in all 20 consecutive patients. The clinical performance of hypnosis showed an 'excellent and good' control for 69% of maintenance time, and the controller performance showed an average global performance index of 57. The clinical performance of analgesia was 'excellent and good' for 92% of maintenance time, and the controller performance showed a global performance index of 1118. CONCLUSIONS: Transcontinental anaesthesia is feasible; control of anaesthesia shows good performance indexes. Clinical registration number NCT01331096.

Evaluation of a novel closed-loop total intravenous anaesthesia drug delivery system: a randomized controlled trial.

BACKGROUND: We have developed an automatic anaesthesia system for closed-loop administration of anaesthesia drugs. The control variables used were bispectral index (BIS) and Analgoscore for hypnosis and antinociception, respectively. METHODS: One hundred and eighty-six patients were randomly enrolled in two groups. Propofol, remifentanil, and rocuronium were administered using closed-loop feedback control (closed-loop, n = 93) or manually (control group, n = 93). The clinical performance of hypnosis control was determined by calculating the offset from a BIS of 45: 'excellent', 'good', 'poor', and 'inadequate' control was defined as BIS values within 10%, from 11% to 20%, from 21% to 30%, or >30% offset from the target. The clinical performance of analgesia was defined as the offset from Analgoscore values. Data presented as mean (standard deviation) (95% confidence interval). RESULTS: Excellent or good control of hypnosis was achieved significantly longer in the closed-loop group [47.0 (9.8%) (45.0/49.0), 34.4 (4.7%) (33.5/35.4)] than in the control group [37.3 (14.3%) (34.4/40.2) and 32.3 (7.6%) (30.7/33.7)], respectively (P<0.0001 and 0.0085). Poor and inadequate control of hypnosis was significantly shorter in the closed-loop group [10.8 (5.0%) (9.8/11.8) and 7.7 (6.2%) (6.4/9.0)] than in the control group [14.7 (6.8%) (13.3/16.0) and 15.8 (14.7%) (12.8/18.8)], respectively (P<0.0001). Excellent control of analgesia was achieved significantly longer in the closed-loop group [78.7 (16.2%) (75.4/82.0)] than in the control group [73.7 (17.8%) (70.1/77.3)] (P=0.0456). CONCLUSIONS: The closed-loop system was better at maintaining BIS and Analgoscore than manual administration.

First robotic tracheal intubations in humans using the Kepler intubation system.

BACKGROUND: Intubation is one of the most important anaesthetic skills. We developed a robotic intubation system (Kepler intubation system, KIS) for oral tracheal intubation. METHODS: In this pilot study, 12 patients were enrolled after approval of the local Ethics board and written informed consent. The KIS consists of four main components: a ThrustMaster T.Flight Hotas X joystick (Guillemot Inc., New York, NY, USA), a JACO robotic arm (Kinova Rehab, Montreal, QC, Canada), a Pentax AWS video laryngoscope (Ambu A/S, Ballerup, Denmark), and a software control system. The joystick allows simulation of the wrist or arm movements of a human operator. The success rate of intubation and intubation times were measured. RESULTS: Eleven men and one woman aged 66 yr were included in this study. Intubation was successful in all but one patient using KIS at a total time of [median (inter-quartile range; range)] 93 (87, 109; 76, 153) s; in one patient, fogging of the video laryngoscope prevented intubation using KIS. CONCLUSIONS: We present the first human testing of a robotic intubation system for oral tracheal intubation. The success rate was high at 91%. Future studies are needed to assess the performance and safety of such a system.

Early protected motion after extensor tendon repair.

Thirty hands with 50 extensor tendon lacerations, excluding mallet finger injuries, were examined. They were treated with surgical repair followed by immediate motion which included a dynamic splinting and tendon mobilization program. The average follow-up period was 7 months (range, 8 weeks to 2 years). Forty-five of the 50 tendons regained full range of motion (average total active motion, 262 degrees) within an average time of 9 weeks; the remaining 5 tendons had extension lags of < or = 10 degrees. All patients regained at least 93% of their predicted normal strength within 9 to 12 weeks and returned to their previous level of activity in an average of 10 weeks. These results, which include complex lacerations, are an improvement from previously published data. This is probably due to the addition of a tendon mobilization program to dynamic splinting following extensor tendon repair.

Field trials of a vaccine against bovine mastitis. 2. Evaluation in two commercial dairy herds.

A vaccine against bovine mastitis was developed. The vaccine was based on inactivated, highly encapsulated Staphylococcus aureus cells; a crude extract of Staph. aureus exopolysaccharides; and inactivated unencapsulated Staph. aureus and Streptococcus spp. cells. In this study, the vaccine was evaluated in 164 cows from two commercial dairies (A and B) during a 4-mo period. Two doses of the vaccine were administered subcutaneously to 82 cows in the brachiocephalicus muscle of the neck within a 4-wk interval. The results of this trial revealed significantly fewer intramammary infections caused by Staph. aureus at various levels of severity (clinical, subclinical, and latent) in cows that were vaccinated. The odds ratios of all types of intrammammary infections caused by Staph. aureus for dairies A and B, which were determined by a logistic model, were 1.84 and 1.89, respectively, for quarters of vaccinated cows and quarters of control cows. The colony counts for Staph. aureus in milk from infected quarters of vaccinated cows were significantly lower than those in milk from infected quarters of control cows. Also, the somatic cell counts per milliliter in milk from vaccinated cows were significantly decreased when the initial somatic cell count was < 500,000 cells/ml at the start of the trial. The vaccine had no observable effect on fat production in milk or on streptococcal infections.

Early motion after hand and wrist reconstruction.

There is substantial evidence to support the fact that early motion is beneficial for bones, joints, ligaments, tendons, and muscles. An Early Mobilization Program was designed to provide early motion for all these structures after hand and wrist reconstruction.

Early motion protocols in hand and wrist rehabilitation.

Early motion programs establish gliding, decrease unwanted adhesions, and enhance the healing process and return to normal function of injuries. This article elaborates on how to best incorporate early motion programs into the rehabilitation process.

Early motion after extensor tendon surgery.

Early motion programs for extensor tendon lacerations and repairs are relatively new and are proving to be extremely beneficial in the rehabilitation process. This article discusses when these programs are indicated and the details of how to provide a good early motion program.

Early motion after wrist surgery.

This article reviews general considerations for therapists when initiating early motion after wrist surgery. Various early range of motion techniques and splinting are discussed in detail for the radiocarpal joint and distal radioulnar joint.

Ulnar shortening using the AO small distractor.

Twenty-four patients (24 wrists) with ulnar impaction syndrome underwent ulnar shortening osteotomy. They were reviewed retrospectively to evaluate a technique using the AO small distractor and 2.7-mm dynamic compression plate. A transverse osteotomy using an external compression device and compression plating was performed in all cases. The average follow-up time was 32 months. Clinical and radiographic union occurred at an average of 9.7 weeks. There were no nonunions. This study demonstrates that ulnar transverse shortening osteotomy with external compression and plating is a simple and effective method of ulnar shortening, and that highly precise and complex instrumentation is not essential.

Anatomy of the extensor mechanism of the hand and wrist.

This article describes extensor muscle and tendon anatomy from origin to insertion. As usual, the use of appropriate terminology is the building block for understanding the function and disorders of the extensor mechanism.

Extensor physiology in the hand and wrist.

The Physiology of finger extension is complex because of the various components of the extensor tendon mechanism. This article discusses the role each component plays in finger extension. Tendon excursion, strength, and electromyographic activity of the extensors are discussed.

Hand strength: normative values.

We studied normal hand strength and the difference between dominant and nondominant hands. Two hundred fourteen volunteers were tested with a calibrated Jamar dynamometer at all five levels. A pinch gauge was used to assess key and pulp pinch. Height, weight, sex, hand dominance, and hobby demands were predictive of maximum grip. Mean maximum grip for women was 81 lb. and for men was 137 lb. Key pinch averaged 22%, while pulp pinch averaged 16% of maximum grip. Only 129 (60%) patients had maximum strengths at level 2. The majority of right-handed subjects were 10% stronger in grip strength on the dominant side. In left-handed subjects, mean grip was the same for both hands; the nondominant hand was stronger in 50% of left-handed subjects.

Tendon graft anatomy and harvesting.

Tendon grafts are often needed in reconstructive surgery. The choice of a tendon graft donor site should be based on the type of graft needed and knowledge of donor-site anatomy, whether normal or aberrant. This study, based on the dissection of 120 cadavers, describes anatomic variations and tendon harvesting techniques.