Immunotherapy for Epstein-Barr virus-associated cancers

Epstein-Barr virus (EBV)-associated lymphoproliferative disease (EBV-LPD) is a frequently fatal complication of organ transplantation and human immunodeficiency virus (HIV) infection. We have studied the safety and efficacy of adoptively transferred, gene-marked virus-specific cytotoxic T lymphocytes (CTLs) as prophylaxis and treatment of EBV-LPD in recipients of T-cell-depleted allogeneic bone marrow. In 42 patients treated prophylactically, no toxicity was experienced. None of these patients developed EBV-LPD, in contrast with eight of 53 (15%) patients who did not receive prophylactic CTL. Three patients who had not received CTL developed aggressive disease and received CTL as treatment. Gene-marked CTL homed to tumor sites and selective accumulation of marker gene was detected in tumor tissues. Tumors regressed completely in two patients, but the third died of respiratory failure. Infused CTLs persisted for up to 3 years in vivo, they rapidly reconstituted EBV-specific immune responses to levels seen in normal individuals, and they reduced high viral titers by two to three logs. We are now using autologous EBV-specific CTL to treat patients with relapsed EBV-positive Hodgkin's disease and we are developing methods for the generation of antigen-specific lines. This approach could be applied to patients with HIV who develop EBV-LPD, using CTL derived early in the course of HIV infection.     

Gene therapy for hemophilia: feasible in principle but not yet clinically applicable]

The current treatment of haemophiliacs consists of injection of concentrates of blood clotting factors VIII (haemophilia A) and IX (haemophilia B). The inconvenience of the multiple injections needed, and the risk of transmission of infectious agents (HIV, hepatitis) prompted the development of alternative therapies. Gene therapy aims at introducing functional factor VIII and IX genes into the body cells of patients in order to make these cells produce the desired clotting factors. There are two strategies for gene therapy: (a) in the laboratory cells of the patient may be provided with the desired gene, followed by reintroduction of the cells that now produce factor VIII, into the patient (ex vivo strategy); (b) vectors with the desired genes may be injected into the patient in order to induce the modification (in vivo strategy) For both routes, the formal proof-of-principle has been acquired recently in animal experiments: cells modified by factor VIII or IX genes will produce adequate concentrations of the clotting products in plasma and will correct the bleeding tendency. Before the clinical evaluation and widespread application of the technology can be considered many technical problems have to be solved.     

Intra-articular calcaneal fractures: effect of open reduction and internal fixation on the contact characteristics of the subtalar joint

Intra-articular calcaneal fractures are associated with significant long-term morbidity, and considerable controversy exists regarding the optimum method of treating them. The contact characteristics in the intact subtalar joint were determined at known loads and for different positions of the ankle and subtalar joint, using pressure-sensitive film (Super Low; Fuji, Itochu Canada Ltd, Montreal, Quebec). We measured the contact area to joint area ratio (pressure > 5 kg force/cm2 [kgf/cm2]) which normalizes for differences in joint size and the ratio of high pressure zone (>20 kgf/cm2) as a reflection of overall increase in joint pressure. Three simulated fracture patterns were then created and stabilized with either 1 or 2 mm of articular incongruity. Eight specimens were prepared with a primary fracture line through the posterior facet, eight with a joint depression-type fracture, and six with a central joint depression fracture. A measure of 1 to 2 mm of incongruity in the posterior facet for all three fracture patterns produced significant unloading of the depressed fragment, with a redistribution of the overall pattern of pressure distribution to parts of the facet that were previously unloaded.     

Antenatal glucocorticoid administration increases corticotrophin-releasing hormone in maternal plasma

OBJECTIVES: To examine associations between medical and functional variables and at-fault car crashes in a cohort of older drivers. DESIGN: A case-control study. SETTING: A tertiary care medical center. PARTICIPANTS: Older drivers (ages 55-90 years) residing in Jefferson County, Alabama (n = 174). Cases were drivers who had at least one at-fault crash in the previous 6 years; controls were crash-free during the same period. MEASUREMENTS: Self-reported medical conditions, reported and observed functional measures, and urinary drug screens. The occurrence of one or more at-fault car crashes in the 6 years preceding the 1991 assessment date represented the outcome measure. RESULTS: Ninety-nine older drivers experienced between one and seven at-fault vehicle crashes during the period 1985 through 1991, whereas 75 drivers did not. Logistic regression models indicated that the following variables were independently associated with crash involvement: A 40% or greater reduction in the useful field of view (OR = 6.1; 95% CI, 2.9 to 12.7; P < 0.001), black race (OR = 6.6; 95% CI, 1.7 to 26.2; P = .007), a history of falling in the previous 2 years (OR = 2.6; CI, 1.1 to 6.1; P = .025), and not taking a beta-blocking drug (OR = 4.3; CI, 1.2 to 15.0; P = .023). CONCLUSIONS: Functional assessments, such as a comprehensive test of visual processing, a falls history, and a review of current medications may be of greater relevance than specific medical conditions in the identification of older at-risk drivers. If prospective studies determine that falling and crashing share risk factors, a unified approach to the prevention of these mobility disorders could result. The finding of an independent association of black race with at-fault crashing is in need of further clarification because of the low representation of black drivers in this sample.     

Synthesis of a potent wide-spectrum serotonin-, norepinephrine-, dopamine-reuptake inhibitor (SNDRI) and a species-selective dopamine-reuptake inhibitor based on the gamma-amino alcohol functional group

Mortality data for B6CF1 mice exposed to 60Co gamma rays for the duration of life were used to make quantitative predictions of age-specific mortality observed in comparably exposed beagles. Simple Kaplan-Meier survival curves for the beagles and their 95% confidence intervals were computed for each dose-rate group observed. A dose-response equation was estimated from the mortality data for mice using a proportional hazard model. The dose-response model for mice was then used to generate predicted survivorship curves at dose rates that would recreate the dose burdens observed in the beagle at comparable points within the life span of the two organisms. When these predicted survivorship curves were scaled to adjust for species differences in the life span of control animals, the predictions for the mouse fell within the confidence intervals observed for the beagle. The successful interspecies extrapolation of age-specific mortality risks for species as different as the mouse and dog enhances both the value of studies involving laboratory animals and the potential relevance of the animal studies to the prediction of health effects in humans.     

Efficacy of azithromycin in the treatment of cyclosporine-induced gingival hyperplasia in renal transplant recipients

BACKGROUND: Gingival hyperplasia (GH) is a common side effect of cyclosporine . Azithromycin (Zithromax; AZI) is a macrolide antibiotic reported in case studies to reduce cyclosporine-induced gingival hyperplasia (CIGH) in renal transplant recipients (RTR). METHODS: The efficacy of AZI to treat CIGH in RTR was examined in a double-blind, randomized crossover trial. Patients (n=17) with CIGH were randomized to receive AZI and a matching placebo in alternate order for 5 days, separated by a 2-week washout period. Follow-up visits were conducted at week 6 and week 12. Changes in GH were evaluated by measuring the clinical gingival sulcus depths, tooth length, and the length of the interdental papillae to the cementum-enamel junction of two teeth in each of the four quadrants. RESULTS: Significant improvements were observed in all three types of periodontal measurements, representing reductions of gingival tissue above the medial aspect of the tooth, of the gingival sulcus depth, and of the length of the interdental papillae. Patients reported an improvement in gum bleeding. AZI was well tolerated, and 67% of the patients reported that the treatment was at least somewhat useful. CONCLUSIONS: AZI should be considered for RTR with CIGH.     

Size- and invasion-dependent increase in cyclooxygenase 2 levels in human colorectal carcinomas

Nonsteroidal anti-inflammatory drugs reduce the incidence and mortality of colorectal carcinoma. Their chemopreventive effects appear to be due to inhibition of cyclooxygenase (COX)-2. Here, we have studied the relationship between the COX-2 mRNA levels and pathological characteristics in 43 primary colorectal carcinomas. COX-2 levels were significantly higher in tumors with larger sizes and in those with deeper invasions but were not correlated with whether the patients had metastasis or not. These results suggest that larger carcinomas produce more COX-2 to support their own growth and that COX-2 inhibitors may be effective agents of carcinoma growth suppression.     

Prostaglandin E1 improves pulsatile preservation characteristics and early graft function in expanded criteria donor kidneys

Unlike simple cold storage, machine preservation allows dynamic assessment and manipulation of the donor organ before transplantation. The effects of four pharmacologic agents added to the perfusate during machine preservation of expanded criteria donor (ECD) kidneys were prospectively compared to 1) describe their influence on perfusion parameters and 2) determine their influence on early graft outcome. Between 1 January 1995 and 1 October 1997, 125 consecutive ECD kidneys were preserved in the authors' laboratory. A definition of ECD was assigned to kidneys requiring pretransplant biopsy. The ECD kidneys were randomized to receive prostaglandin E1 (PGE1), trifluoperazine (TFP), verapamil (VER), mannitol (MAN), or no intervention (control) during machine preservation. All kidneys were preserved by continuous hypothermic pulsatile perfusion (CHPP) using Belzer II solution, and perfusion parameters were measured every 2 hours during pulsatile perfusion. The addition of PGE1 to the perfusate increased renal flow and decreased renal resistance. Moreover, the PGE1 treated group was associated with improved early graft function when compared with all other groups. The addition of VER, TFP, and MAN influenced neither the perfusion characteristics nor the incidence of early graft function. Treatment with PGE1 during machine preservation enhances hydrostatic perfusion parameters (renal flow and renal resistance) and reduces the incidence of delayed graft function in ECD kidneys.