Autocrine growth of human blymphocytes: Maintained response to autostimulatory factors is the special feature of immortalization by Epstein-Barr virus—A hypothesis

The autocrine growth profile of human B lymphocytes transformed with Epstein-Barr virus (EBV) was found to comprise three distinct components: a B-cell growth factor (BCGF); an interleukin-1 (IL-1)-like activity; an activity requiring cell-to-cell contact for its action. Observations on the inhibition of the EBV-carrying Daudi lymphoma line by α-interferon indicated that loss of response to these autostimulatory factors was underlying growth cessation. Furthermore, a putative for BCGF was found to be down-regulated on B cells stimulated with non-transforming mitogens but constitutively expressed following EBV-transformation. Taken together with recent evidence that normal B cells produce autostimulatory factors, these findings suggest that the special feature of autocrine growth by EBV-immortalized cells is a maintenance of what should normally be a transient phenotype, possibly through deregulation of receptor expression. This hypothesis is discussed.     

Prediction of drug disposition kinetics in skin and plasma following topical administration

The development of a physically based pharmacokinetic model for percutaneous absorption is described. The simulation includes four first-order rate constants assigned the following significance: (a) absorption across the stratum corneum; (b) diffusion through the viable tissue; (c) a retardation process which retains penetrant in the stratum corneum (and hence provides a means to mathematically produce a "reservoir" effect, for example); and (d) uptake from the skin into the systemic circulation and subsequent elimination from the body. The kinetic equations of the model are solved and expressions are obtained for the concentration of penetrant within the stratum corneum (and available to subsequently partition into the viable epidermis) and the plasma concentration of the administered substance, as a function of time. Using example values for the four rate parameters, disposition profiles for the penetrant in skin and plasma were derived. The cases considered cover slow and fast stratum corneum penetrants, substances which are excreted rapidly or slowly from the body, and absorbing molecules with a variety of relative stratum corneum-viable tissue affinities. The results suggest a framework for the prediction of pharmaceutically and clinically relevant information following the topical administration of therapeutic agents for local or systemic effect.     

Micronutrients and Markers of Oxidative Stress and Inflammation Related to Cardiometabolic Health: Results from the EHES-LUX Study

Metabolic syndrome (MetS) characteristics include chronic inflammation and elevated oxidative stress. This study assessed associations between circulating concentrations of micronutrients/phytochemicals and inflammatory/oxidative stress markers with MetS and MetS components. Adults (N = 606) from the European Health Examination Survey in Luxembourg (2013–2015) were randomly selected. We performed a multivariable logistic regression model using the least absolute shrinkage and selection operator to identify MetS-associated variables. Participants with MetS had higher concentrations of C-reactive protein (CRP), 8-iso-prostaglandin F2α, leptin, insulin, and vitamins E/A, but lower concentrations of adiponectin, beta-carotene, and oxidized low-density lipoprotein. A one-unit increase in log-CRP was associated with 51% greater odds of MetS (OR = 1.51 (95% CI: 1.16, 1.98)). Adults with a one-unit increase in log-leptin were 3.1 times more likely to have MetS (3.10 (2.10, 4.72)). Women with a one-unit increase in vitamin A were associated with 3% increased odds of MetS (1.03 (1.01, 1.05)), while those with a one-unit increase in log-adiponectin were associated with 82% decreased odds (0.18 (0.07, 0.46)). Chronic inflammation best characterized adults with MetS, as CRP, adiponectin, and leptin were selected as the main MetS determinants. Micronutrients did not seem to affect MetS, except for vitamin A in women.     

Human Diversity of Killer Cell Immunoglobulin-Like Receptors and Human Leukocyte Antigen Class I Alleles and Ebola Virus Disease Outcomes

We investigated the genetic profiles of killer cell immunoglobulin-like receptors (KIRs) in Ebola virus–infected patients. We studied the relationship between KIR–human leukocyte antigen (HLA) combinations and the clinical outcomes of patients with Ebola virus disease (EVD). We genotyped KIRs and HLA class I alleles using DNA from uninfected controls, EVD survivors, and persons who died of EVD. The activating 2DS4–003 and inhibitory 2DL5 genes were significantly more common among persons who died of EVD; 2DL2 was more common among survivors. We used logistic regression analysis and Bayesian modeling to identify 2DL2, 2DL5, 2DS4–003, HLA-B-Bw4-Thr, and HLA-B-Bw4-Ile as probably having a significant relationship with disease outcome. Our findings highlight the importance of innate immune response against Ebola virus and show the association between KIRs and the clinical outcome of EVD.     

Evaluating bowel enterotomy closures in simulated deep body cavities using the reversing half-hitch alternating post and square knots: a randomized controlled trial

BackgroundSquare knots can be difficult to construct in deep body cavities. The reversing half-hitch alternating post (RHAP) surgical knot has noninferior tensile strength and performance characteristics in deep body cavities. We compared the enterotomy repairs of novice learners in simulated deep body cavities using RHAP versus square knots after proficiency-based training.MethodsUndergraduate students were randomized to RHAP (n = 10) or square knot (n = 10) groups and trained to defined proficiency. They then performed hand-sewn enterotomy repairs of cadaveric porcine small bowels on flat surfaces and in simulated deep body cavities. We recorded time to knot-tying proficiency and to enterotomy repair, and burst pressures for the repair.ResultsMean time-to-proficiency in knot tying was equivalent between the RHAP and square knot groups (23 [standard deviation (SD) 3] v. 21 [SD 2] min, p = 0.33). Mean time for enterotomy repair in deep cavities was shorter for the RHAP group (16 [SD 2] min v. 21 [SD 1] min, p = 0.02). Mean burst pressures for enterotomy repair were equivalent on flat surfaces (128 [SD 41] v. 101 [SD 36] mm Hg, p = 0.31), and were significantly higher for the RHAP group in simulated deep body cavities (32 [SD 13] v. 105 [SD 37] mm Hg, p = 0.05).ConclusionThe RHAP knots appear to have superior performance versus square knots when tied in a deep body cavity by novice learners. Future work should focus on demonstrating the clinical relevance and broad utility of the RHAP knot in abdominal surgery. Both knot types should be taught to novice learners.     

Efficient propagation of single gene deleted recombinant Sendai virus vectors

Recombinant Sendai virus vectors (SeVV) have become an attractive tool for basic virological as well as for gene transfer studies. However, to (i) reduce the cellular injury induced by basic recombinant SeV vectors (encoding all six SeV genes as being present in SeV wild-type (wt) genomes) and to (ii) improve SeV vector safety, deletions of viral genes are necessary for the construction of superior SeVV generations. As a strong expression system recombinant replication-incompetent adenoviruses, coding for SeV proteins hemagglutinin-neuraminidase (HN), fusion (F), or matrix (M), were generated and successfully employed for the propagation of single gene deleted (DeltaHN, DeltaF, DeltaM) recombinant SeVV. Further investigations of the propagation procedures required for single gene deleted recombinant SeVV demonstrated (i) modifications of the cell culture medium composition as well as (ii) incubation with vitamin E as crucial steps for the enhancement of SeVV-DeltaHN, -DeltaF, or -DeltaM viral particle yield. Such optimized propagation procedures even led to a successful propagation of HN-deleted viral particles (SeVV-DeltaHN), which has not been reported before.     

Examination of stratum corneum barrier function in vivo by infrared spectroscopy

It is generally accepted that the stratum corneum (SC) is the least permeable layer of the epidermis. Histologically, though, the SC is a non-uniform, inhomogeneous membrane, and the question "Is barrier function distributed uniformly across the SC thickness?" has been posed. To address this issue, human ventral forearm SC has been studied in vivo by attenuated-total-reflectance Fourier-transform infrared spectroscopy during the course of sequential tape-stripping. Because the intercellular lipids of the SC and the degree of hydration of the membrane have been shown to be crucial determinants of barrier function, attention has been focused on the spectral features, which report specifically on these parameters. The degree of disorder of the SC intercellular lipids has been found to decrease over the outer cell layers (up to three tape-strips) and then to remain essentially constant. The amount of lipids decreases similarly such that a 60% reduction (relative to the "no-strip" baseline) is observed after about four tape-strips. A plausible explanation for these measurements is that the lipids near the surface are a mixture of (a) "true" intercellular lipid (which is expected to be highly ordered), and (b) sebaceous lipid (which contains much greater amounts of low-melting components, such as fatty acids). The sequential infrared (IR) spectra provide at least circumstantial evidence to support this hypothesis. As expected, the IR spectra show that SC hydration increases from the surface towards the SC-stratum granulosum interface. Taken together, the results imply that the SC is indeed non-uniform. The properties of the outer layers (those removed by the first 3-4 tape-strips) change significantly with increasing depth.(ABSTRACT TRUNCATED AT 250 WORDS)     

Early phase II Gynecologic Oncology Group experience with ifosfamide/mesna in gynecologic malignancies

Starting in July 1985, the Gynecologic Oncology Group conducted a series of phase II trials with ifosfamide/mesna in advanced or recurrent gynecologic malignancies. Previously untreated patients received 1.5 g/m² i.v. ifosfamide daily for 5 days. Mesna was given i.v. q4h×3 following ifosfamide; each dose was 20% of the daily ifosfamide dose. All patients with ovarian and 87% of those with cervical cancer had previously undergone platinum-based therapy. Because of the toxicity encountered in previously treated patients with ovarian carcinoma, the dose of ifosfamide was reduced to 1.2 g/m² daily in all patients who had received prior chemo- or radiotherapy. In epithelial ovarian carcinoma, responses were observed in 8 (20.0%) of 41 evaluable patiens, with 3 (7.0%) complete responses. Response duration was 2.1–20.3+ months, with a median of 6.9+ months. In squamous-cell carcinoma of the cervix, 3 (11.1%) of 27 evaluable patients showed partial responses of 1.8, 2.2, and 3.1 months' duration. Of 26 untreated patients with mixed mesodermal tumors of the uterus, 5 (19.2%) achieved complete and 3 (11.5%) showed partial responses, for an overall response rate of 30.7%. Response duration was 1.4+-8.6 months, with a median of 3.8 months. Toxicity included two deaths due to renal insufficiency and a third related to neurologic impairment. Hematologic toxicity was manageable. Ifosfamide/mesna has activity in a wide range of gynecologic malignancies.Presented at the Satellite Symposium Ifosfamide in Gynecological Tumors of the 5th European Conference on Clinical Oncology and Cancer Nursing, London, September 3–7, 1989