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.
Therapeutic strategies based on modulation of microRNA (miRNA) activity hold great promise due to the ability of these small RNAs to potently influence cellular behavior. In this study, we ...investigated the efficacy of a miRNA replacement therapy for liver cancer. We demonstrate that hepatocellular carcinoma (HCC) cells exhibit reduced expression of miR-26a, a miRNA that is normally expressed at high levels in diverse tissues. Expression of this miRNA in liver cancer cells in vitro induces cell-cycle arrest associated with direct targeting of cyclins D2 and E2. Systemic administration of this miRNA in a mouse model of HCC using adeno-associated virus (AAV) results in inhibition of cancer cell proliferation, induction of tumor-specific apoptosis, and dramatic protection from disease progression without toxicity. These findings suggest that delivery of miRNAs that are highly expressed and therefore tolerated in normal tissues but lost in disease cells may provide a general strategy for miRNA replacement therapies.
Previous research has demonstrated that a brief course on pain management improved knowledge and attitudes toward analgesic use among medical students. The purpose of this study is to compare a ...structured clinical instruction course on regional anesthesia techniques for perioperative pain management with traditional teaching given to senior medical students.
During a 1-month clerkship in anesthesiology, 40 fourth-year medical students were randomly and equally divided into 2 groups. The study group received a 2-hour structured course on regional anesthesia techniques for pain management, whereas the control group received a 1-hour lecture tutorial on regional anesthesia techniques for perioperative pain management and 1 hour of bedside teaching on acute pain management. Each student completed an objective structured clinical examination (OSCE) 2 weeks after completion of the course.
The study group performed better on each of the 11 items of the OSCE and on the total performance scores (mean +/- SD of 36.2 +/- 7.3 for study group versus 14.8 +/- 8.4 for the control group; P < .05). All students rated the clinical course highly valuable (4.7 +/- 0.5).
A structured clinical instructional course on regional techniques for perioperative pain management given to fourth-year medical students can significantly improve their understanding and knowledge compared with traditional teaching.
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.
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.
Patients are more than customers Montgomery, C L
The American journal of nursing,
09/1988, Letnik:
88, Številka:
9
Journal Article
Recenzirano
Patients expect a lot more out of nurses than drawing blood and fluffing pillows. A patient expects a nurse to apply her knowledge and experience to evaluate his requests in terms of his own best ...interests. Nurse-patient relations are discussed.
The hospital employee as patient Montgomery, C L
The American journal of nursing,
12/1987, Letnik:
87, Številka:
12
Journal Article
Recenzirano
Various issues confronting hospital personnel who get sick and are forced to choose between going to the hospital that employs them or choosing another institution are discussed.
Taming a tyrant Montgomery, C L
The American journal of nursing,
02/1987, Letnik:
87, Številka:
2
Journal Article
Recenzirano
The problem nurses face when dealing with a tyrannical doctor is described. Some advice on how to deal with the problem without losing your temper and making the situation worse, and without taking ...too much unfounded abuse is given.
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