Accountability in health care--transplant community offers leadership.

Two concerns expressed by the American Society of Transplant Surgeons (ASTS) are that (1) the new Medicare regulations for transplant hospitals take a 'punitive' approach and that (2) the outcome requirement may thwart innovation by not including certain risk factors into the risk adjustment used to calculate expected outcomes. This article explains efforts by the Centers for Medicare & Medicaid Services (CMS) to encourage quality improvement. CMS limits outcomes-related enforcement to situations where failure rates exceed certain substantial 'tolerance limits', ensuring opportunity for quality improvement to be effective prior to enforcement. Transplantations involving a disproportionate share of risk factors not incorporated into the risk-adjustment methodology can also be raised through CMS''mitigating factors' process. Of the 22 mitigating factor requests completed through March 10, 2009, 7 raised issues of risk adjustment (none involved experimental protocols). Four of the seven requests were approved for other reasons (evidence of effective program changes and improved outcomes). CMS concluded that none of the seven made a persuasive case based on risk factors. The early data indicate that program deficiencies may outweigh risk adjustment issues. CMS agrees to consider the ASTS suggestions for future action and continues to monitor the situation in case a different pattern emerges.

Effect of adenoviral early genes and the host immune system on in vivo pancreatic gene transfer in the mouse.

Gene transfer technology may provide a novel approach to treatment for pancreatic diseases. Recombinant adenovirus achieves efficient gene transfer in vivo. In this study, a murine model of adenoviral-mediated pancreatic gene transfer was developed, and the factors responsible for adenoviral elimination were investigated. Three days after direct pancreatic injection of a replication-defective adenovirus containing the lacZ transgene, a high proportion (76.8 +/- 6.7%) of pancreatic cells expressed beta-galactosidase, the gene product. Gene expression was absent by 28 days posttransduction. In immunodeficient mice, beta-galactosidase expression persisted with 20.0 +/- 6.0% of pancreatic cells staining positive 60 days after viral transduction. To test whether early viral proteins are the antigenic components responsible for the potent antiviral immune response, normal mice were injected with different adenoviral vectors containing early gene deletions. Vectors containing deletions in early region 2 or 4 expressed beta-galactosidase at 28 days. Presently available adenoviral vectors engineered to avoid this response offer minimal improvements in transgene duration. Further vector modifications or alternative strategies are needed to achieve stable pancreatic adenoviral transgene expression.

Functional consequences of adenovirus-mediated murine pancreatic gene transfer.

Pancreatic adenoviral gene transfer can be achieved with high efficiency; however, questions concerning tissue injury from this commonly used vector have not been addressed. In these experiments, the effects of adenoviral gene transfer on pancreatic exocrine function were evaluated. Direct pancreatic injection with an adenoviral vector containing the Escherichia coli beta-galactosidase (beta-Gal; lacZ) transgene (H5.010CBlacZ) resulted in a high level of transgene expression (64 +/- 6% of pancreatic cells expressed beta-Gal) at 3 days following infection. However, amylase levels in four of five different subcellular pancreatic fractions were significantly decreased at this time point. Direct pancreatic injection with either saline or psoralen/UV-inactivated adenovirus did not have this effect, whereas both transduction with an adenoviral vector containing a different transgene and transduction with a homologous transgene resulted in decreased pancreatic amylase. The decrease in subcellular amylase levels persisted at 7 days post-transduction, and then returned to baseline at 21 days post-transduction. There was associated histologic damage (increased edema, inflammation, cell destruction, and vacuolization) at 3 and 7 days post-transduction, which resolved by 21 days. In summary, adenoviral transduction of the pancreas results in increased viral transgene expression and a uniform decrease in host amylase production throughout the pancreas. The normalization of amylase levels and histology suggest that organ recovery occurs. Gene transfer technology as a novel strategy for pancreatic diseases such as diabetes, pancreatitis, and cystic fibrosis is feasible but will benefit from continued approaches to limit toxicity.

Efficient adenoviral-mediated murine neonatal small intestinal gene transfer is dependent on alpha(v) integrin expression.

BACKGROUND/PURPOSE: Clinical application of gene therapy for patients who have inflammatory bowel disease or short bowel syndrome will require the development of new strategies to improve the efficiency of small intestinal gene transfer. Previously, the authors developed a method for adenoviral-mediated small intestinal gene transfer in vivo in neonatal and adult mice. The present study evaluates the hypothesis that the integrins alpha(v)beta3 and alpha(v)beta5, the secondary receptors for adenoviral internalization, play a facilitative role in neonatal murine adenoviral-mediated small intestinal gene transfer. METHODS: Immunohistochemical techniques identified the integrin alpha(v)beta3 and the integrin subcomponents alpha(v), beta3, and beta5 in neonatal and adult small intestine. The effects of integrin receptor antagonists on transgene expression was also studied in our neonatal model of adenoviral-mediated small intestinal gene transfer in vivo. RESULTS: Gene transfer was significantly decreased by the addition of integrin receptor antagonists versus control peptide. Integrin alpha(v)beta3 and integrin subcomponent alpha(v), beta3, and beta5 are expressed in neonatal and adult small intestine. Integrin antagonists administered simultaneously blocked efficient adenoviral-mediated neonatal small intestinal gene transfer in vivo compared with control peptide. CONCLUSION: Strategies to upregulate integrin expression may improve adenoviral-mediated small intestinal gene transfer.

How issues of professional liability are taught in U.S. medical schools.

This study investigated how medicolegal issues--specifically those concerning professional liability--are treated in U.S. medical school education. The author mailed a questionnaire in mid-1989 to all 127 U.S. medical schools that were accredited at that time and to the five medical school campuses of the University of Illinois; 120 (90%) responded. Of these, 73 (61%) reported that they included topics about professional liability in their educational curricula. Twenty-three of the schools indicated that students' training had been "compromised or jeopardized" by the impact of physicians' concerns about medicolegal issues. Forty-seven of the schools had students who had been named in malpractice suits. The study shows that undergraduate medical education has been significantly affected by issues of professional liability. Relevant medicolegal content should be an integral part of medical school education.

Thyroid neoplasia in Marshall Islanders exposed to nuclear fallout.

We studied the risk of thyroid neoplasia in Marshall Islanders exposed to radioiodines in nuclear fallout from the 1954 BRAVO thermonuclear test. We screened 7266 Marshall Islanders for thyroid nodules; the islanders were from 14 atolls, including several southern atolls, which were the source of the best available unexposed comparison group. Using a retrospective cohort design, we determined the prevalence of thyroid nodularity in a subgroup of 2273 persons who were alive in 1954 and who therefore were potentially exposed to fallout from the BRAVO test. For those 12 atolls previously thought to be unexposed to fallout, the prevalence of thyroid nodules ranged from 0.9% to 10.6%. Using the distance of each atoll from the test site as a proxy for the radiation dose to the thyroid gland, a weighted linear regression showed an inverse linear relationship between distance and the age-adjusted prevalence of thyroid nodules. Distance was the strongest single predictor in logistic regression analysis. A new absolute risk estimate was calculated to be 1100 excess cases/Gy/y/1 X 10(6) persons (11.0 excess cases/rad/y/1 million persons), 33% higher than previous estimates. We conclude that an excess of thyroid nodules was not limited only to the two northern atolls but extended throughout the northern atolls; this suggests a linear dose-response relationship.

The formation of functional penicillin-binding proteins.

A method was developed which permitted determination of the [14C]benzylpenicillin and [14C]Cephapirin binding capacity of rapidly growing Bacillus subtilis cells in liquid culture. Over the concentration range of the binding plateau (0.1 to 0.8 mug/ml), [14C]benzylpenicillin significantly inhibited formation of functional penicillin-binding proteins, but had comparatively little effect on total bacterial protein synthesis. The data suggest that penicillin covalently bound to the cells in a chemically stable manner alone is not sufficient to inhibit formation of functional binding proteins and that unbound penicillin in the growth medium is necessary. The concentration of unbound antibiotic in the culture medium, in turn, is a function of the cell-bound penicillinase activity whose significance increases with cell density. [14C]Cephapirin, a cephalosporin resistant to this cell-bound penicillinase almost completely inhibited the formation of functional Cephapirin-binding proteins, but had relatively little effect on total protein synthesis. At concentrations 250-fold higher than that required to inhibit formation of functional binding proteins. Cephapirin did not inhibit particulate D-alanine carboxypeptidase activity and presumably did not bind covalently to this penicillin-binding protein.

Accessibility of the (14C)benzylpenicillin binding proteins in membranes of sporulating bacilli.

Triton X-100 treatment or freeze-thawing damages the membranes of sporulating or vegetative cells as seen by protein leakage from cells. A 40% increase in the specific [(14)C]benzylpenicillin-binding capacity of detergent-treated or frozen sporulating cells was observed. Neither freezing nor Triton X-100 treatment of vegetative cells produced a detectable effect on their [(14)C]benzylpenicillin-binding capacity. These data indicate the presence of penicillin-binding sites in intact sporulating bacilli not accessible to penicillin in routine binding assays. The chemical specificity of [(14)C]benzylpenicillin binding to detergent-treated sporulating cells is similar to that observed with untreated vegetative or sporulating cells.