In VivoStudies of Adenovirus-Based p53 Gene Therapy for Ovarian Cancer

Objectives.To test the safety, efficacy, and toxicity of gene therapy using wild-type p53-expressing adenovirus (Ad-CMV-p53) in a nude mouse model with intraperitoneal (ip) 2774 human ovarian cancer cell line that contains a p53 mutation.Study design.An initial study of adenovirus tolerance was determined in nude mice by a single ip injection of increasing doses of Ad-CMV-p53. Nude mice were implanted with an LD₁₀₀dose of 1 × 10⁷cells. To study the efficacy and specificity of Ad-CMV-p53 treatment, the mice received treatment with different adenovirus constructs. One group received Ad-CMV-p53 and another group received a control adenovirus construct, Ad-CMV-βgal. To study the treatment response to Ad-CMV-p53, the mice were divided into groups and received various treatment schedules of 1 × 10⁸pfu of Ad-CMV-p53.Results.The mice tolerated Ad-CMV-p53 without adverse effects at doses of 1 × 10⁸pfu. The response to Ad-CMV-p53 showed significant survival duration in each dose regimen, with a survival time greater than that of untreated animals (P= 0.0173). However, no statistically significant survival advantage was observed between Ad-CMV-p53- and Ad-CMV-βgal-treated mice.Conclusions.These studies show that at the adenovirus dose and administration regimen used, there is effective but not specific 2774 tumor growth inhibitionin vivo.Efficient introduction of biologically active genes into tumor cells would greatly facilitate cancer therapy. Thus, although promising, these results caution that much effort will be required to realize the potential for clinical application of adenovirus-based ovarian cancer gene therapy.     

Evidence of an abnormal intramuscular component of fatigue in multiple sclerosis

The goals of this study were to investigate muscle fatigue in patients with multiple sclerosis (MS), and to determine the relationships between muscle fatigue, clinical status, and perceived fatigue. The fatigability of the anterior tibial muscle was quantitated in patients and controls during 9 min of intermittent stimulation (used to eliminate central sources of muscle fatigue). During exercise, the decline in tetanic force, phosphocreatine, and intracellular pH was greater in patients than in controls. The compound muscle action potential amplitude did not decrease during exercise, indicating that there was no failure of neuromuscular transmission during fatigue. Thus, the excessive fatigue in MS developed from sources beyond the muscle membrane. Following exercise, the recovery of tetanic force was delayed in patients (a pattern that suggests abnormal excitation–contraction coupling), whereas the recovery of metabolites was complete in both groups. Muscular fatigue was correlated with clinical disability but not with perceived fatigue. These results suggests that fatigue in MS has both central (perception, upper motor neuron dysfunction) and peripheral (impaired metabolism and excitation–contraction coupling) components.© 1995 John Wiley &Sons, Inc.     

Assessment of sexual abuse and trauma: Clinical measures

Examined are several measures currently used in the assessment of child abuse, sexual abuse, and trauma. These measures include structured clinical interviews, self report measures, screening inventory, symptom checklist, and some measures that include decision making properties. Issues and implications for clinical practice are explored.     

Bladder leiomyosarcoma following cyclophosphamide therapy for lupus nephritis

We report 2 cases of leiomyosarcoma of the bladder that occurred after long-term cyclophosphamide chemotherapy for lupus nephritis and rheumatoid arthritis. One patient had a tumor at the end of an 11-year course of chemotherapy and 1 approximately 7 years after completing a 7-year course of chemotherapy. Patient 1 underwent left partial cystectomy and patient 2 underwent cystectomy with ileal conduit urinary diversion. In patient 1 the tumor was a typical leiomyosarcoma and patient 2 had a myxoid variant. Both patients were free of disease at 4 months and 3 years, respectively. Whereas previous reports of the carcinogenic effects of cyclophosphamide have been questioned, since the induced tumors occurred in patients being treated for other neoplasms (lymphoproliferative and myeloproliferative disorders), the disease in both of our patients followed cyclophosphamide therapy for nonneoplastic disorders.     

The ileal neobladder: experience and results of more than 100 consecutive cases

The ileal neobladder produces a completely detubularized, low pressure, high capacity reservoir constructed from ileum without any valves. From April 1986 through May 1989, 113 patients underwent this procedure at our institution. Of these patients 99 underwent simultaneous radical cystectomy for bladder cancer and 14 underwent bladder augmentation. The mean postoperative followup was 14.4 months, with a range of 1 to 36 months. There was no perioperative mortality. However, 7 patients died more than 2 months postoperatively: 5 of tumor progression, 1 of pneumonia and severe metabolic acidosis, and 1 of septicemia of unknown cause. Reoperation was necessary in only 13 patients; 10 patients required urethrotomy or dilation of urethral strictures. Day and night continence was preserved in 82.1% of all patients. Stress incontinence, which must be corrected by an artificial sphincter, was found in 4 patients (4.2%) and night-time incontinence that required an external device occurred in 5 (5.3%). Eight patients (8.4%) with mild stress incontinence required no further treatment. Pressure waves exceeding 22 cm. water seldom occurred and then only at maximum capacity. Our experience with this relatively simple system without a nipple is an overwhelming success. The need for reoperation is extraordinarily low and the high reservoir capacity results in continence from the beginning in most patients. The concept is sound and offers a genuine alternative to any form of cutaneous urinary diversion with an incidence of complications not higher than after standard supravesical urinary diversion.     

Human selenium status and glutathione peroxidase activity in north-west England

Nutritional selenium deficiency disease, due to low soil selenium content, is well recognized in British livestock. The adequacy of the selenium status of 25 healthy human volunteers, 50 blood donors, 94 general medical patients and 106 allergy clinic patients was investigated in 1987/8 by measuring serum selenium concentration and platelet glutathione peroxidase activity. Mean serum selenium concentration for the entire study population was 92 micrograms/l. Significant linear correlations between serum selenium concentration and peroxidase activity indicate that a substantial proportion of both healthy volunteers and medical patients are of low selenium nutritional status. Twenty-five per cent of healthy volunteers and 50 per cent of medical patients had serum selenium values below those required for full expression of selenium-dependent enzyme activity. Deficiency of the antioxidant activities of selenium and selenium-dependent enzymes may be relevant to geographical differences in morbidity from a wide range of human disease states.     

Microbiological and pharmacokinetic studies of acyl demycinosyltylosin and related tylosin derivatives

A series of tylosins and acyl derivatives of 23-O-demycinosyltylosin (DMT) were initially tested for in vitro antibacterial activity and serum levels in squirrel monkeys (po) and mice (iv). Overall, the DMT compounds were more active in vitro than the tylosins. Two tetraacylated DMTs, Sch 37644 and Sch 38646, were selected from the initial studies for further evaluation and compared to erythromycin and A-56268 (6-O-methyl erythromycin). Sch 37644 and Sch 38646 were 2 to 8-fold less potent in vitro against Gram-positive bacteria than erythromycin and A-56268. In squirrel monkeys, Sch 37644 (AUC, 19.7 micrograms.hour ml) and A-56268 (21.6 micrograms.hour/ml) had similar serum levels following po administration of 20 mg/kg, while Sch 38646 (11.8 micrograms.hour/ml) and erythromycin (1.5 micrograms.hour/ml) had lower levels. In mice administered 200 mg/kg orally, Sch 37644 (AUC, 19.4 micrograms.hour/ml) and Sch 38646 (15.4 micrograms.hour/ml) had higher serum levels than erythromycin (5.7 micrograms.hour/ml). A-56268 was the most active po macrolide in mouse protection studies (PD50S) against Staphylococci and Streptococci, while Sch 37644 and Sch 38646 were similar to erythromycin.