Liver allotransplantation after extracorporeal hepatic support with transgenic (hCD55/hCD59) porcine livers: clinical results and lack of pig-to-human transmission of the porcine endogenous retrovirus

BACKGROUND: Whole organ extracorporeal perfusion of a genetically modified humanized (transgenic) pig liver has been proposed as a technology that may sustain patients with severe liver failure while awaiting human liver transplantation. METHODS: We report on two cases of successful extracorporeal perfusion of a transgenic pig liver in patients awaiting transplantation for fulminant hepatic failure. The pig livers used were transgenic for human CD55 (decay-accelerating factor) and human CD59. These transgenic modifications are designed to reduce or eliminate the hyperacute rejection inherent in pig-to-primate xenotransplants. We also report on the results of serial surveillance testing for presence of the porcine endogenous retrovirus (PoERV) in these two patients. RESULTS: Extracorporeal perfusion in two patients was performed for 6.5 and 10 hr, respectively, followed by the successful transplantation of a human liver and resultant healthy patients (18 and 5 months later as of this writing). The porcine livers showed evidence of synthetic and secretory function (decreasing protime and bilirubin, bile production). Serial polymerase chain reaction analysis of these patients' peripheral blood mononuclear cells has failed to show presence of PoERV DNA sequences. CONCLUSIONS: The CD55/CD59 transgenic porcine liver appears capable of safely "bridging" a patient to liver transplantation. Human PoERV infection from these livers has yet to be demonstrated.     

Prevention of ovarian cancer: intraepithelial neoplasia.

To reduce the incidence and mortality associated with invasive cancers, the Intraepithelial Neoplasia (IEN) Task Force recommends that carcinogenesis be viewed as a disease that requires treatment. This publication outlines the current knowledge of IEN of the ovary and reviews chemoprevention possibilities for ovarian cancer. Ovarian cancer has the highest mortality of all of the gynecological cancers and is the fourth leading cause of death from cancer in women. The IEN Task Force has defined precancer as a noninvasive lesion that has genetic abnormalities, loss of cellular control functions, and some phenotypic characteristics of invasive cancer with a substantial likelihood of developing invasive cancer. The IEN Task Force recommends targeting moderate to severe dysplasia for new IEN treatment agents in clinical trials. Ovarian cancer does not have a clear preinvasive lesion yet merits considerable study for new prevention strategies because of the high mortality associated with ovarian cancer. There is a great unmet clinical need for treatments that can prevent ovarian cancer by providing nonsurgical options that treat the entire epithelial layer. New prevention strategies hold significant promise to reduce the mortality from ovarian cancer.     

Predictive testing for BRCA1 and 2 mutations: a male contribution.

BACKGROUND: Management strategies for women carrying BRCA1 and 2 mutations are becoming clearer and predictive testing for a known family mutation is commonly undertaken. Implications for men are not as clear and they participate less frequently. PATIENTS AND METHODS: Twenty-six men from 10 extended families underwent predictive testing. Their motivation, reaction and outcome were studied. Subjects had appropriate pre- and post-test counselling. Informed consent was obtained before predictive testing for known deleterious mutations. DNA analysis followed standard procedures. RESULTS: Eighteen tested positive and eight negative. Four had adverse psychological reactions and three reneged on their commitments to impart results. The spouse of another man had an adverse psychological reaction to the disclosure of his positive result. Two, already suffering from prostate cancer, were phenocopies and paternal lineage transmission was unexpectedly determined in another. Risk was removed from 33 offspring and confirmed for 56. CONCLUSIONS: Complex themes associated with genetic testing are confirmed and the spectrum extended. Men appear to understand the importance of participating in this process. Methods of avoiding adverse reactions merit further study along with other aspects of the process.     

Effect of stride length on symptoms of exercise-induced muscle damage during a repeated bout of downhill running

The purpose of this study was to assess the effects of changes in stride length on the symptoms of exercise-induced muscle damage (EIMD) during a repeated bout of downhill running in a group of 18 men and women. Muscle tenderness, plasma creatine kinase activity (CK) and maximal voluntary isometric force were measured before and after two downhill runs, with each run separated by 5 weeks. The first downhill run was at the preferred stride frequency (PSF). Participants were then randomly allocated to one of three sex-balanced groups with equal numbers of men and women: overstride (-8% PSF), understride (+8% PSF) and normal stride frequency for the second downhill run. Stride length had no effect (P>0.05) on muscle tenderness, CK or isometric peak force. Increases in muscle tenderness (P<0.001) and CK were lower (P<0.05) following the second downhill run, although there was no difference in the pattern and extent of the strength decrement between the two runs. There were also no differences (P>0.05) in muscle tenderness, CK or the relative strength loss between the men and the women. Results suggest that the symptoms of EIMD are unaffected by gender and small alterations to the normal stride pattern during constant velocity downhill running. The observation that muscle tenderness and CK were reduced following a repeated bout of similar eccentric exercise is consistent with the phenomenon known as the 'repeated bout effect' of muscle damage.     

Reorganizing the system of care surrounding laparoscopic surgery: a cost-effectiveness analysis using discrete-event simulation.

PURPOSE: To determine the cost-effectiveness of a proposed reorganization of surgical and anesthesia care to balance patient volume and safety. METHODS: Discrete-event simulation methods were used to compare current surgical practice with a new modular system in which patient care is handed off between 2 anesthesiologists. A health care system's perspective, using hospital and professional costs, was chosen for the cost-effectiveness analysis. Outcomes were patient throughput, flow time, wait time, and resource use. Sensitivity analyses were performed on staffing levels, mortality rates, process times, and scheduled patient volume. RESULTS: The new strategy was more effective (average 4.41 patients/d [median = 5] v. 4.29 [median = 4]) and had similar costs (average cost/ patient/d = 5327 dollars v. 5289 dollars) to the current strategy with an incremental cost-effectiveness of 318 dollars/additional patient treated/d. Surgical mortality rate must be >4% or hand-off delay >15 min before the new strategy is no longer more effective. CONCLUSION: The proposed system is more cost-effective relative to current practice over a wide range of mortality rates, hand-off times, and scheduled patient volumes.     

Nasal carriage of methicillin-resistant Staphylococcus aureus in an American Indian population.

BACKGROUND AND OBJECTIVE: Although reports of methicillin-resistant Staphylococcus aureus (MRSA) infections without healthcare exposure are increasing, population-based data regarding nasal colonization are lacking. We assessed the prevalence of and risk factors for community-associated MRSA nasal carriage in patients of a rural outpatient clinic. DESIGN: A cross-sectional population survey was conducted through random sample and stratification by community of residence. Recent healthcare exposure (ie, hospitalization, dialysis, or healthcare occupation) and other risk factors for MRSA carriage were assessed. Cultures of the nares were performed. Community-associated MRSA was defined as MRSA carriage without healthcare exposure. SETTING: A predominantly American Indian community in Washington. PATIENTS: Those receiving healthcare from an Indian Health Service clinic. RESULTS: Of 1,311 individuals identified for study, 475 (36%) participated. Unsatisfactory culture specimens resulted in exclusion of 6 participants. In all, 128 (27.3%) of 469 participants had S. aureus. Nine (1.9%) of 469 had MRSA carriage; of these, 5 had community-associated MRSA (5 of 469; overall community-associated MRSA carriage rate, 1.1%). MRSA carriage was associated with antimicrobial use in the previous year (risk ratio [RR], 7.2; P = .04) and residence in a household of more than 7 individuals (RR, 4.5; P = .03). Pulsed-field gel electrophoresis indicated that 5 (55%) of 9 MRSA carriage isolates were closely related, including 3 (60%) of 5 that were community associated. CONCLUSIONS: Prevalence of community-associated MRSA colonization was approximately 1% in this rural, American Indian population. Community-associated MRSA colonization was associated with recent antimicrobial use and larger household.