Plasmapheresis eliminates the negative impact of AAV antibodies on microdystrophin gene expression following vascular delivery.

Duchenne muscular dystrophy is a monogenic disease potentially treatable by gene replacement. Use of recombinant adeno-associated virus (AAV) will ultimately require a vascular approach to broadly transduce muscle cells. We tested the impact of preexisting AAV antibodies on microdystrophin expression following vascular delivery to nonhuman primates. Rhesus macaques were treated by isolated limb perfusion using a fluoroscopically guided catheter. In addition to serostatus stratification, the animals were placed into one of the three immune suppression groups: no immune suppression, prednisone, and triple immune suppression (prednisone, tacrolimus, and mycophenolate mofetil). The animals were analyzed for transgene expression at 3 or 6 months. Microdystrophin expression was visualized in AAV, rhesus serotype 74 sero-negative animals (mean: 48.0 ± 20.8%) that was attenuated in sero-positive animals (19.6 ± 18.7%). Immunosuppression did not affect transgene expression. Importantly, removal of AAV binding antibodies by plasmapheresis in AAV sero-positive animals resulted in high-level transduction (60.8 ± 18.0%), which is comparable with that of AAV sero-negative animals (53.7 ± 7.6%), whereas non-pheresed sero-positive animals demonstrated significantly lower transduction levels (10.1 ± 6.0%). These data support the hypothesis that removal of AAV binding antibodies by plasmapheresis permits successful and sustained gene transfer in the presence of preexisting immunity (natural infection) to AAV.

Problem-Based Learning in Anesthesiology: An Evaluative Study of a Medical Student Clerkship.

BACKGROUND: Problem-based learning (PBL) in medical education has enjoyed widespread acceptance in recent years, particularly in the basic sciences. However, it has been used less frequently in the clinical education of medical students, and quite infrequently in medical student education on anesthesiology. Critics of PBL emphasize cost factors and a lack of evidence of superior educational outcomes. METHODS: This study reports evaluation data on the use of PBL with fourth year medical students who rotated through a required clerkship in clinical anesthesiology and pharmacology over the course of three academic years. Students were asked to complete evaluation questionnaires concerning the clerkship, with particular attention to PBL and the performance of PBL preceptors. Preceptors were also asked to self-rate their performance by using identical questionnaires. Standardized items across all three years facilitated analysis of student and faculty satisfaction as one outcome of the PBL process. RESULTS: Results indicate that student response to PBL was mixed. Students rated PBL preceptors more favorably than the PBL process itself, and rated resident physician preceptors more favorably than attending physician preceptors. All preceptors rated their own performance lower than did their students. Significant differences between student and faculty opinion of PBL were also noted. Interpretation of results are limited by less than ideal response rates; nevertheless, valuable insight was gained into the perception of PBL in an anesthesiology clerkship. CONCLUSIONS: The success of this educational method may be dependent upon certain factors related to "educational context". Further study is needed of contextual and other factors related to the use of PBL in medical education.

Coping with the emotional demands of caring.

A grounded theory investigation produced a model for how caregivers are affected by the experience of caring. Whether nurses felt fulfilled by caring or traumatized by the risks of personal loss and emotional overload was determined by the meanings they were able to create from the experience. These meanings were derived from both inner personal resources as well as contextual resources. Positive meanings produced an alchemical effect described as a "peak experience," which reinforced engagement and the commitment to caring. Negative meanings associated with emotional depletion and trauma lead to disengagement and withdrawal from caring. Implications are discussed.

A prospective study of rectal methohexital: efficacy and side effects in 648 cases.

Rectal methohexital has been used for nearly 30 yr in pediatric anesthesia. Despite this long and increasingly varied use, no large prospective series has been published detailing safety and efficacy. This study prospectively evaluated the efficacy, safety, and side effects of this medication in a series of 648 cases. On 553 of 648 occasions (85%), the child fell asleep after a single 30-mg/kg dose of 10% methohexital. Sleep was less likely in patients with myelomeningocele or who were receiving oral phenobarbital or phenytoin. When sleep occurred, the average time to onset of sleep was 6 min. Most patients who remained awake 15 min after drug were sedated. Defecation (10%) and hiccups (13%) were common but benign side effects. Partial airway obstruction and/or desaturation to Spo2 < or = 93% occurred in 26 patients (4%), but was resolved with blow-by oxygen and/or jaw-thrust in all but two cases. These two patients (0.3% of total) required aggressive airway intervention by the supervising anesthesiologist. Apnea did not occur in any patient. Methohexital has a high efficacy rate for sleep (85%) or sedation (96%), and has a relatively rapid onset. Significant respiratory side effects occur infrequently, but can be life threatening if not properly managed.

Cardiorespiratory effects of premedication for children.

Cardiovascular and respiratory effects of pediatric preanesthetic premedication have received only minimal attention, probably because most children tolerate such drugs without apparent ill effect. In children with congenital heart disease or other serious illness, there is often reluctance to use premedication. We sought to determine whether different premedication regimens produced significant cardiorespiratory effect. A randomized prospective study of the cardiovascular and respiratory effects of different oral, nasal, and rectal premedication regimens was conducted. Fifty-eight young children (average age 2.7 yr) were studied. Oral meperidine (3 mg/kg) with pentobarbital (4 mg/kg) decreased heart rate, mean arterial pressure, cardiac index, respiratory rate, and oxygen saturation. Stroke volume was maintained. Nasal ketamine (5 mg/kg) with midazolam (0.2 mg/kg) produced no significant cardiovascular or respiratory effects. Rectal methohexital (30 mg/kg) increased heart rate with a coincident decrease in stroke volume but had no other positive or negative cardiac or respiratory effect. This information documents disparate cardiorespiratory effects of different preanesthetic medications in normal children.

Caring, curing, and brief therapy: a model for nurse-psychotherapy.

Traditional models of psychotherapy have failed to meet the demands for accessible, cost-effective, and accountable mental health services. This traditional approach to mental health based on the received view of science is deconstructed in terms of its cure-orientation and contrasted with the care-orientation of nursing that is more consistent with postmodern ideas of science. Methods of brief, intermittent or possibility-oriented therapy are suggested as ways to actualize a care-orientation to mental health nursing that is more consistent with nursing's values and is more accessible to the needs of the consumer.

Application of the Mizus endotracheal obturator in tracheostomy and tentative extubation.

A variety of catheters, stylets, and obturators have been used to assist with problems in airway management. Obturators specifically designed for airway use are now available in different sizes. The pediatric-size obturators (2.2 mm diameter) can be placed into the airways of most patients without apparent respiratory impairment. Use of these obturators to preserve a path to the airway is described in cases of tracheostomy and tentative extubation. The advantages and disadvantages inherent in the use of such obturators are described.

In vitro activity of N-formimidoyl thienamycin (MK0787), a crystalline derivative of thienamycin.

N-Formimidoyl thienamycin (MK0787) is a derivative of thienamycin, a unique, new beta-lactam antibiotic. Its activity against 285 aerobic and facultatively anaerobic clinical isolates was compared with the activities of cephalothin, ampicillin, penicillin G, ticarcillin, and tobramycin. All of the 285 isolates, with the exception of 1 Staphylococcus epidermidis isolate, were inhibited by a concentration of N-formimidoyl thienamycin of less than or equal to 8 micrograms/ml. More than 50% of all isolates were inhibited by the lowest concentration of N-formimidoyl thienamycin tested (0.125 micrograms/ml); 98% of Staphylococcus aureus and 80% of S. epidermidis isolates were inhibited by N-formimidoyl thienamycin at a concentration of 0.125 micrograms/ml. Only 2 of 45 enterococci were not inhibited by 1 microgram of N-formimidoyl thienamycin per ml, and this drug was the most active agent tested against 162 gram-negative bacilli. It inhibited more than 95% of the gram-negative isolates at a concentration of less than or equal to 2 micrograms/ml. N-Formimidoyl thienamycin was as active or more active than tobramycin against Escherichia coli, Pseudomonas aeruginosa, and Proteus mirabilis and substantially more active than ticarcillin. All 16 isolates of Klebsiella pneumoniae were inhibited by less than or equal to 0.5 micrograms of N-formimidoyl thienamycin per ml. The marked in vitro activity of this drug against a wide variety of clinical isolates makes it a promising new antibiotic.