The use of 19F spectroscopy and diffusion-weighted MRI to evaluate differences in gene-dependent enzyme prodrug therapies.

To evaluate noninvasive measures of gene expression and tumor response in a gene-dependent enzyme prodrug therapy (GDEPT), a bifunctional fusion gene between Saccharomyces cerevisiae cytosine deaminase (CD) and Haemophilus influenzae uracil phosphoribosyltransferase (UPRT) was constructed. CD deaminates 5-fluorocytosine (5FC) to 5-fluorouracil (5FU), and UPRT subsequently converts 5FU to fluorouridine monophosphate, and both of these reactions can be monitored noninvasively in vitro and in vivo using 19F magnetic resonance spectroscopy (MRS). Following transient transfection the CD-UPRT fusion protein exhibited both UPRT and CD enzymatic activities as documented by 19F MRS. In addition, an increase in CD activity and thermal stability was witnessed for the fusion protein compared to native CD. Stable expression of CD-UPRT in 9L glioma cells increased both 5FC and 5FU sensitivity in vitro compared to CD-expressing and wild-type 9L cells. Noninvasive 19F MRS of both CD and UPRT gene function in vivo demonstrated that in animals bearing CD-expressing tumors there was limited conversion of 5FC to 5FU with no measurable accumulation of cytotoxic fluorinated nucleotides (F-nucs). In contrast, CD-UPRT-expressing tumors had increased CD gene activity with a threefold higher intratumoral accumulation of 5FU and significant generation of F-nucs. Finally, CD-UPRT yielded increased efficacy in an orthotopic animal model of high-grade glioma. More importantly, early changes in cellular water mobility, which are felt to reflect cellular death, as measured by diffusion-weighted MRI, were predictive of both durable response and increased animal survival. These results demonstrate the increased efficacy of the CD-UPRT GDEPT compared to CD alone both biochemically and in a preclinical model and validate both 19F MRS and diffusion-weighted MRI as tools to assess gene function and therapeutic efficacy.     

Outcomes of Project Wall Talk: an HIV/AIDS peer education program implemented within the Texas State Prison system.

We report select outcomes from an evaluation of Project Wall Talk, a community-based, peer-led HIV prevention education program implemented in 36 Texas State prison units. Peer educators completed questionnaires prior to receipt of a 40-hour intensive training (N = 590) and at 9-month follow-up (N = 257). Students (N = 2506) completed questionnaires pre- and post-receipt of peer educator-led HIV education sessions. Peer educators and their students showed significant increases in HIV-related knowledge. Peer educators showed significant increases in assessment of their skills as educators. For both peer educators and students, significant differences in HIV-related knowledge were indicated across categories of prior educational level attained and race/ethnicity; no such differences were indicated at follow-up. Compared with baseline, a significantly greater proportion of peer educators reported ever having had an HIV test. After receiving peer-led education, a significantly smaller proportion of students reported they knew their HIV status and more indicated plans to take an HIV test. Additionally, in months 12 and 18 following program implementation, the numbers of HIV tests at the five units that implemented the peer education program were roughly twice that of five, matched comparison units without the peer education program. Based on peer educator reports, we projected that peer educators (N = 257) may have as many as 84,000 or more annual opportunities to share HIV-related knowledge with other prisoners outside the classroom.     

Quality of life and exercise performance in patients in sinus rhythm versus persistent atrial fibrillation: a Veterans Affairs Cooperative Studies Program Substudy.

OBJECTIVES: The purpose of this study was to determine quality of life (QOL) and exercise performance (EP) in patients with persistent atrial fibrillation (AF) converted to sinus rhythm (SR) compared with those remaining in or reverting to AF. BACKGROUND: Restoration of SR in patients with AF improving QOL and EP remains controversial. METHODS: Patients with persistent AF were randomized double-blind to amiodarone, sotalol, or placebo. Those not achieving SR at day 28 were cardioverted and classified into SR or AF groups at 8 weeks (n = 624) and 1 year (n = 556). The QOL (SF-36), symptom checklist (SCL), specific activity scale (SAS), AF severity scale (AFSS), and EP were assessed. RESULTS: Favorable changes were seen in SR patients at 8 weeks in physical functioning (p < 0.001), physical role limitations (p = 0.03), general health (p = 0.002), and vitality (p < 0.001), and at 1 year in general health (p = 0.007) and social functioning (p = 0.02). Changes in the scores for SCL severity (p = 0.01), functional capacity (p = 0.003), and AFSS symptom burden (p < 0.001) at 8 weeks and in SCL severity (p < 0.01) and AF symptom burden (p < 0.001) at 1 year showed significant improvements in SR versus AF. Symptomatic patients were more likely to have improvement. The EP in SR versus AF was greater from baseline to 8 weeks (p = 0.01) and to 1 year (p = 0.02). The EP correlated with physical functioning and functional capacity except in the AF group at 1 year. CONCLUSIONS: In patients with persistent AF, restoration and maintenance of SR was associated with improvements in QOL measures and EP. There was a strong correlation between QOL measures and EP.     

The role of coronary angioplasty in the management of unstable angina pectoris

Using percutaneous transluminal coronary angioplasty (PTCA) as primary therapy for unstable angina is quite common. Unstable angina appears to be the indication for the procedure in approximately one third of all PTCA attempts. Considering the unstable nature of the plaque in this type of angina, and the increased risk of abrupt occlusion due to frequent intraluminal thrombus, the generally reported rate of success, approximately 85%, is highly respectable. The evidence supporting a period of pretreatment with aspirin and heparin is strong. Less certain is the value of concomitantly administering plasminogen activators. Pending data should produce important further guidelines for effective therapy. Major trials, some using fibrinolytics as well as taking an overall aggressive, interventional approach (like that taken by UNSA, TIMI-III, and others), are reaching the recruitment-completion and promulgation stages.     

Geriatric trauma: resource use and patient outcomes.

INTRODUCTION: Elderly patients who suffer trauma have a higher mortality and use disproportionately more trauma resources than younger patients. To compare these 2 groups and determine the outcomes and characteristics of elderly patients, we reviewed patients in these 2 groups admitted and treated in our tertiary care provincial trauma centre. METHODS: From the provincial trauma registry we selected a cohort of 40 geriatric patients (group 1) (> or = 65 yr of age) with an ISS of 16 or more who were admitted to and spent time in our trauma service for more than 48 hours and compared them with a similar randomly selected cohort of 44 patients (group 2) aged 20-30 years. Family physicians were contacted for follow-up of these patients 2 years after discharge. We considered length of hospital stay, complications, disposition of the patients and use of consultation services. RESULTS: Patients in group 1 had a mean age of 72.1 years (range from 65-98 yr) and a mean ISS of 27.3 (range from 17-50). Patients in group 2 had a mean age of 26.3 years (range from 22-29 yr) and a mean ISS of 26.3 (range from 17-54). Hospital stay was significantly longer in the group 1: 34.5 days (95% confidence interval [CI]: 24-44 d) versus 21.6 days (95% CI: 15-28 d). More elderly patients experienced complications (35 v. 13, p < 0.001) and required medical consultations (35 v. 26, p < 0.001). In-hospital death rates were 8% (3 of 40) and 4% (2 of 44) respectively (p = 0.3). Fewer geriatric patients could be discharged home (35% [14 of 40] v. 27% [22 of 44], p = 0.056) or to rehabilitation facilities (28% [11 of 40] v. 34% [15 of 44], p = 0.3). Five geriatric patients were discharged to nursing homes (p = 0.007). Of the geriatric patients discharged to rehabilitation facilities or home, 75% were independent 2 years after discharge. CONCLUSIONS: Aggressive care for geriatric trauma patients is warranted, and resources should be directed toward rehabilitation. Based on our findings, we expect that creating a directed care pathway for these patients, targetting complications and earlier discharge, will further improve their outcomes.     

Management of older patients presenting after a fall--an accident and emergency department audit.

BACKGROUND: It is common for older patients to present to accident and emergency (AE) departments after a fall. Management should include assessment and treatment of the injuries and assessment and correction of underlying risk factors in order to prevent recurrent falls. OBJECTIVES: To determine management of older patients presenting after a fall to the AE department of Groote Schuur Hospital in Cape Town, South Africa. METHOD: Hospital records were reviewed for a random sample of 100 patients aged 65 years and older presenting to the AE department after a fall, between December 2001 and May 2002. RESULTS: The mean age of the sample was 78.6 years (range 65-98 years); 72% of subjects were female. History of a previous fall, and history of drug or alcohol intake, were recorded in less than 20% of cases. Blood pressure and pulse rate were recorded in approximately 90% of cases, and pulse rhythm and postural blood pressure in 2%. Examination of the musculoskeletal system was done in 86% of cases and that of other systems in less than 50%; cognitive assessment was conducted in less than 30%. Radiological investigations were performed in 89% of cases, glucose and haemoglobin in 32%, renal profile and electrocardiogram in 5%, and urinalysis in 4%. Three-quarters of the patients were referred for further management: 52% to orthopaedic surgery, 12% to other surgical subspecialties, 6% to the general medical department, and 6% to other hospitals and clinics. No referrals were made to geriatric medicine, physiotherapy or occupational therapy. CONCLUSIONS: In managing elderly patients after a fall, the AE department focused on injuries sustained. Little effort was made to establish and manage risk factors, hence to prevent recurrent falls. Guidelines are needed for the management of such patients in AE departments.     

To thin or not to thin: the use of the anterolateral thigh flap in the reconstruction of intraoral defects.

The anterolateral thigh (ALT) flap has achieved popularity recently for free-flap reconstruction of intraoral defects following excision of squamous cell carcinoma. We have assessed the feasibility of the ALT flap as a free flap for oral lining and the potential use of the thinned ALT flap in a one-stage reconstruction. We used the ALT flap to reconstruct the oral cavity in 18 consecutive patients between December 2000 and December 2001 following intraoral resection of squamous cell carcinoma. Twelve patients underwent reconstruction using a standard ALT flap, four patients received a thinned ALT flap in a one-stage procedure, one patient received a standard ALT flap in combination with a fibula flap and one patient received a combination of a standard ALT flap and vascularised iliac bone. There were no complications in any of the 14 cases in which a standard ALT flap was used. Two of these flaps were thinned subsequently as secondary procedures. Of the four thinned ALT flaps, one flap failed completely and two flaps experienced partial necrosis. In all but one case the donor site was closed directly with minimal donor-site morbidity. The ALT flap is a versatile flap that can be used in combination with other flaps for more complex defects with minimal donor-site morbidity and is a useful alternative in the armamentarium of the head and neck surgeon. Thinning of the flap is best performed as a secondary procedure, should it be required.