Citations

There is a major deficiency in the end-of-life care offered to patients dying in the intensive care unit (ICU). Hypothesis: Hospitalized dying patients had informed discussions on endof-life and palliative care options before admission to ICU. Patients and methods: A descriptive non-interventional study was performed at a teaching hospital to examine if patients who died in hospital had informed discussions on end-of-life care before admission to ICU. The impact of these discussions on subsequent patient care: aggressive therapy in the ICU, the quality of palliation, use of hospice care services and utilization of hospital resources were examined. Data were collected from medical records for all hospital deaths over 24 months. Results: Of 252 hospital deaths, 196 (78%) were treated and subsequently 165 (65%) died in the ICU. Patients treated either in the ICU or general hospital wards had similar frequency of ultimately or rapidly fatal pre-existing disease (47% versus 62%, P: ns) and readmission to hospital within one year before death (43% versus 57%, P, ns). The median age (10-90% percentile) was slightly younger for the ICU than hospital wards patients: 73 (45-85) versus 76 (55-91) years, PB / 0.01. Of the 156 patients who were transferred to ICU from hospital wards: 136 (87%) were managed by house staff on teaching services and 20 (13%) were managed by attending staff hospitalists, PB / 0.01. None of those transferred to the ICU who subsequently died had discussion of palliation or end-of-life care as an alternative treatment. Of those who died who were treated on general wards, 14 (25%) patients had discussion of palliation as an alternative treatment option before death. Do-not-resuscitate decisions were made in 48% of cases two days before death. Patients who were treated in the ICU had more invasive tests performed on them and were less likely to have adequate pain control or referral to hospice care services than on a general ward. Median hospital charge was much higher for patients who received ICU versus general ward care ($33 252 versus $8549, PB / 0.001). Conclusions: Patients who died in the ICU did not have informed discussions of end-of-life or palliative care as an alternative treatment option before admission. The quality of end-of-life care was disrupted for patients with fatal pre-existing chronic disease who were admitted to the ICU before death. Lack of clinical experience, knowledge and competency with end-of-life care influenced admission of patients to ICU regardless of poor prognosis. Decisions regarding the pursuit of aggressive therapy versus palliative care must be addressed with patients by physicians who are competent and experienced in end-of-life care as this will have a profound impact on both the quality of care delivered and effective use of limited hospital resources.

ABSTRACT Inefficient adenoviral vector (AdV)-mediated gene transfer to the ciliated respiratory epithelium has hindered gene transfer strategies for the treatment of cystic fibrosis lung disease. In part, the inefficiency is due to an absence of the coxsackie B and adenovirus type 2 and 5 receptor (CAR) from the apical membranes of polarized epithelia. In this study, using an in vitro model of human ciliated airway epithelium, we show that providing a glycosylphosphatidylinositol (GPI)-linked AdV receptor (GPI-CAR) at the apical surface did not significantly improve AdV gene transfer efficiency because the lumenal surface glycocalyx limited the access of AdV to apical GPI-CAR. The highly glycosylated tethered mucins were considered to be significant glycocalyx components that restricted AdV access because proteolytic digestion and inhibitors of O-linked glycosylation enhanced AdV gene transfer. To determine whether these in vitro observations are relevant to the in vivo situation, we generated transgenic mice expressing GPI-CAR at the surface of the airway epithelium, crossbred these mice with mice that were genetically devoid of tethered mucin type 1 (Muc1), and tested the efficiency of gene transfer to murine airways expressing apical GPI-human CAR (GPI-hCAR) in the presence and absence of Muc1. We determined that AdV gene transfer to the murine airway epithelium was inefficient even in GPI-hCAR transgenic mice but that the gene transfer efficiency improved in the absence of Muc1. However, the inability to achieve a high gene transfer efficiency, even in mice with a deletion of Muc1, suggested that other glycocalyx components, possibly other tethered mucin types, also provide a significant barrier to AdV interacting with the airway lumenal surface.

ABSTRACTThe subgroup A to E avian sarcoma and leukosis viruses (ASLVs) are highly related and are thought to have evolved from a common ancestor. These viruses use distinct cell surface proteins as receptors to gain entry into avian cells. Chickens have evolved resistance to infection by the ASLVs. We have identified the mutations responsible for the block to virus entry in chicken lines resistant to infection by subgroup A ASLVs [ASLV(A)]. Thetvagenetic locus determines the susceptibility of chicken cells to ASLV(A) viruses. In quail, the ASLV(A) susceptibility alleletvasencodes two forms of the Tva receptor; these proteins are translated from alternatively spliced mRNAs. The normal cellular function of the Tva receptor is unknown; however, the extracellular domain contains a 40-amino-acid, cysteine-rich region that is homologous to the ligand binding region of the low-density lipoprotein receptor (LDLR) proteins. The chickentvascDNAs had not yet been fully characterized; we cloned the chickentvacDNAs from two lines of subgroup A-susceptible chickens, line H6 and line 0. Two types of chickentvascDNAs were obtained. These cDNAs encode a longer and shorter form of the Tva receptor homologous to the Tva forms in quail. Two different defects were identified in cDNAs cloned from two different ASLV(A)-resistant inbred chickens, line C and line 72. Line Ctvarcontains a single base pair substitution, resulting in a cysteine-to-tryptophan change in the LDLR-like region of Tva. This mutation drastically reduces the binding affinity of TvaRfor the ASLV(A) envelope glycoproteins. Line 72tvar2contains a 4-bp insertion in exon 1 that causes a change in the reading frame, which blocks expression of the Tva receptor.

The complex modulus E* and elastic modulus E′ of agarose gels (2% to 4%) are measured with a dynamic mechanical analyzer in frequency sweep shear sandwich mode between 0.1 and 20 Hz. The data showed that E* and E′ increase with frequency according to a power law which can be described by a fractional derivative model to characterize the dynamic viscoelasticity of the gel. The functions between the model parameters including storage modulus coefficient H and the power law exponent (β) and the agarose concentration are established. A molecular basis for the application of the fractional derivative model to gel polymers is also discussed. Such an approach can be useful in tissue culture studies employing dynamic pressurization or for validation of magnetic resonance elastography.

The human HtrA family of proteases consists of four members: HtrA1, HtrA2, HtrA3, and HtrA4. In humans the four HtrA homologues appear to be involved in several important functions such as cell growth, apoptosis, and inflammatory reactions, and they control cell fate via regulated protein metabolism. In previous studies it was shown that the expression of HtrA1 was ubiquitous in normal adult human tissues. Here we examined the expression of HtrA1 protein and its corresponding mRNA during mouse embryogenesis using Northern blotting hybridization, RT-PCR, and immunohistochemical staining analyses. Our results indicate that HtrA1 is expressed in a variety of tissues in mouse embryos. Furthermore, this expression is regulated in a spatial and temporal manner. Relatively low levels of HtrA1 mRNA are detected in embryos at the beginning of organogenesis (E8), and the levels of expression increase during late organogenesis (E14-E19). Our results show that HtrA1 was expressed during embryonic development in specific areas where signaling by TGFβ family proteins plays important regulatory roles. The expression of HtrA1, documented both at mRNA and protein levels by RT-PCR and immunohistochemistry in the developing nervous system, is consistent with a possible role of this protein both in dividing and postmitotic neurons, possibly via its documented inhibitory effects on TGFβ proteins. An exhaustive knowledge of the different cell- and tissue-specific patterns of expression of HtrA1 in normal mouse embryos is essential for a critical evaluation of the exact role played by this protein during development.