By Z. Yokian. Wheaton College, Massachusetts. 2018.

Viral promoters were components of many first-generation vectors because they are active in most cell types in vitro order pirfenex 200 mg amex. This loss of function could reflect the absence of transcription factors that are essential for expression of the promoter or the presence of inhibitory proteins that terminate viral promoter activity in nonreplicating cells cheap pirfenex 200mg fast delivery. Internal promoters may also comprise the ubiquitously expressed housekeeping promoters that direct the expression of proteins required by all cells cheap pirfenex 200 mg with mastercard. However, housekeeping genes are often expressed at relatively low levels, and their promoters have been shown to be relatively weak in vitro and in vivo in retroviral vectors constructs. Alternatively, organ-specific promoters have two major advantages: (1) allowing limited expres- sion to specific cell types or tissues and (2) directing high levels of gene expression. Muscle- or liver-specific enhancers and/or promoters, in comparison to housekeep- ing or viral promoters, direct higher levels of expression in vivo. In other studies, however, organ-specific promoters have been inactivated in vivo in transgenic mice or in a retroviral vector by the presence of adjacent retroviral sequences. It is also possible that these inhibitory sequences can decrease expression from adjacent internal promoters. The control of gene expression in vivo may be an appropriate mechanism to decrease variability in expression as well as decrease the chance that the therapeu- tic gene is overexpressed. In clinical situations, variability or overexpression would have adverse therapeutic effects. Inducible expression systems have been developed to tightly regulate expression from a retroviral vector through responsivness to an orally administered drug. However, this system requires the all- important introduction of a drug-responsive transcription factor. This is an addi- tional burden to the individual cell, which needs to receive and express two separate genes. Other factors, in addition to the choice of the promoter, can influence gene expression from a retroviral vector. For some genes and through an unknown mech- anism, the presence of a splice site dramatically increases the level of expression of the protein. Inclusion of genomic splice sites from the therapeutic gene is techni- cally difficult. Through the use of a selectable marker gene and a therapeutic gene, it is possible to eliminate cells not expressing the therapeutic gene by either in vitro or in vivo selection methods. Using these vectors, however, cells selected by virtue of expression of one gene product have a lower level of expression of the second gene product. Risks of Retroviral Vectors There are two major concerns in the use of retroviral vectors for gene therapy in humans: (1) insertional mutagenesis and (2) generation of wild-type virus. Inser- tional mutagenesis occurs when a retroviral vector inserts within or adjacent to a cellular gene. This insertion could result in the development of malignancy through the inactivation of a tumor suppressor gene or by activation of a proto-oncogene. The risk of developing a malignancy through the process of receiving a single copy of a retroviral vector appears to be minimal. The induction of malignancy has not been observed in animals receiving replication-incompetent retroviral vectors. This observed low incidence of mutagenesis indicates that the retroviral vector is unlikely to integrate into a genomic site that will modify cellular growth properties such as cyclins- or cyclin-dependent kinases (see Chapter 10). However, if the vector inserts into a growth-sensitive site, this would represent only the first step in a multistep process. Thus, procedures that introduce multiple retroviral vector integrations into a single cell will only increase the risk of the development of malignancy. A second safety concern regarding retroviral vectors in human use is viral recombination. Tech- nical refinements in vector development have lowered the risk of generating a replication-competent virus. Thus, it is unlikely that replication-competent virus will be administered to humans when the appropri- ate safety controls are observed. It remains possible, however, that a replication- incompetent retroviral vector could recombine with endogenous viruses in vivo. Endogenous viruses are present in vivo and recombination in the human genome can generate additional pathogenic replication-competent virus(es). The occurrence can only be determined by monitoring individual gene therapy recipients for the appearance of replication-competent virus. Summary: Retroviral Vectors Replication-incompetent retroviral vectors can be easily generated by deleting retroviral genes and adding gene(s) of interest. The major advantage of retroviral vectors is the precise integration into a random site in the host cell chromosome. This characteristic poses diffi- culties for the in vivo delivery to quiescent cells. Gene expression at therapeutic levels has been achieved from a retroviral vector in vivo in some studies for over one year, but expression has been problematic in other studies.

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Patients with more severe renal dysfunction or other specific risk factors may benefit from specialist follow-up with a nephrologist [46] while others could be followed-up in primary care and be referred back to renal services if required buy pirfenex 200 mg otc. At this stage patients may require specialist referral generic 200mg pirfenex with amex, or be deemed appropriate for primary care follow-up at a frequency commensurate with their level of renal dysfunction [48] generic 200mg pirfenex mastercard. Thus, even when seen in other (non- nephrology) specialist clinics, renal function is often not assessed. In many cases appropriate long-term follow-up can be accomplished in pri- mary care, but this is only possible if patients are identified and appropriate clinical guidelines are provided by specialists. Robust pathways for monitoring and treating these patients need to be developed and tested. 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Legrand Department of Anesthesiology and Critical Care, Hôpital Européen Georges Pompidou Assistance Publique-Hopitaux de Paris, Sorbonne Paris Cité, Paris , France e-mail: mathieu. Groeneveld Department of Intensive Care Medicine, Erasmus Medical Centre, Doctor Molewaterplein 50-60 , Rotterdam , The Netherlands e-mail: a. Renal blood flow has been estimated by a wide variety of techniques including renal vein thermodilution and Doppler ultrasound [7 – 10]. The most easily applied ultrasound technique, Doppler renal resistive index, provides the pulsatility or resis- tance index in renal arteries and measures renal vascular resistance rather than abso- lute blood flow [11]. Phase contrast-enhanced magnetic resonance imaging is another method [12], but cannot be applied at the bedside. In experimental studies, renal blood flow has also been assessed with the help of microspheres and flow probes around the renal artery, while the renal microcircu- lation has been studied using visualizing techniques [13, 14 ]. In a recent review, renal blood flow during sepsis was either preserved or increased in one-third of the studies included and cardiac output seemed a direct determinant of renal blood flow [15]. However, even in the case of a normal or elevated cardiac output and in the absence of a severe fall in blood pressure, reduction in glomerular filtration may occur as a result of renal vasoconstriction or inflammatory responses [6].