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Although recombinant adenoviruses are attractive vectors for gene transfer to airway epithelia, they have proven to be relatively inefficient. To investigate the mechanisms of adenovirus-mediated gene transfer to airway epithelia, we examined the role of adenovirus fiber and penton base, the two proteins involved in attachment to and entry of virus into the cell. We used human airway epithelia grown under conditions that allow differentiation and development of a ciliated apical surface that closely resembles the in vivo condition. We found that addition of fiber protein inhibited virus binding and vector-mediated gene transfer to immature airway epithelia, as well as to primary cultures of rat hepatocytes and HeLa cells. However, fiber protein had no effect on vector binding and gene transfer to ciliated airway epithelia. We obtained similar results with addition of penton base protein: the protein inhibited gene transfer to immature epithelia, whereas there was no effect with ciliated epithelia. Moreover, infection was not attenuated with an adenovirus containing a mutation in penton base that prevents the interaction with cell surface integrins. These data suggest that the receptors required for efficient infection by adenovirus are either not present or not available on the apical surface of ciliated human airway epithelia. The results explain the reason for inefficient gene transfer and suggest approaches for improvement. ( J. Clin. Invest. 1997. 100: 1144-1149.)
The aim of this study was to characterize the circadian variation of oral tacrolimus disposition in 8 stable liver allograft recipients. In the steady state, a total of 23 blood samples was taken before and after tacrolimus administration during a 24-hr period and the pharmacokinetic parameters were compared. The area under the curve (AUC) of tacrolimus after the morning dose was significantly larger than after the evening dose (211+/-43 ng x hr/ml [morning] vs. 179+/-45 ng x hr/ml [evening], P=0.02). The time to peak (Tmax) was significantly shorter after the morning dose than after the evening dose (1.6+/-0.7 hr [morning] vs. 2.9+/-0.6 hr [evening], P=0.002). The peak (Cmax) was significantly higher after the morning dose than after the evening dose (32.2+/-10.2 ng/ml [morning] vs. 19.1+/-4.3 ng/ml [evening], P=0.003). However, the trough (Cmin) was not significantly different between the morning dose and the evening dose (13.1+/-3.9 ng/ml [morning] vs. 13.3+/-4.4 ng/ml [evening], P=0.4). This study demonstrated that tacrolimus disposition in liver transplant patients was determined by administration time.
As the immunocompromised patient population grows, the gastrointestinal surgeon is increasingly called upon to make complex diagnostic and therapeutic decisions. The surgeon should first identify the patient as immunocompromised and then categorize the probable degree of immunocompromise as mild, moderate, or severe. Mildly immunocompromised patients tend to present late and with minimal symptoms, but the disease entities are the same ones seen in the general population. Moderately and severely immunocompromised patients may also develop the usual surgical problems, but the differential diagnosis is expanded to include complications of the immunocompromised state or complications of the underlying problem which caused the immune compromise. The expanded differential diagnosis includes infections with atypical organisms, opportunistic neoplasms, neutropenic enterocolitis, complications of medications, and forms of biliary tract disease not seen in the general population. Advances in oncology, transplantation, and the treatment of AIDS, have extended the life expectancy of these patients and increased the immunocompromised population. Prompt appropriate operative therapy may be lifesaving when surgical complications develop.
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