Non-specific stimulation of cell-free protein synthesis by a dialyzable factor isolated from reticulocyte initiation factors ("iRNA").

The specificity of a dialyzable component, isolated from rabbit reticulocyte initiation factors, in stimulating protein synthesis was examined. It appeard that his factor (hereafter designated as "iRNA") was able to restore the activity of initiation factor preparations that were inactivated by dialysis. The "iRNA" from reticulocytes stimulated polypeptide synthesis directed by the homologous globin mRNA as well as heterologous lens crystallin mRNAs. No selectivity in its stimulating action with regard to the type of mRNA studied could be observed. The source of ribosomes or supernatant enzymes did not influence the effect of "iRNA". However, in an ascites lysate that was dependent on the addition of initiation factors, "iRNA" increased polypeptide formation only marginally, suggesting that in this lysate a similar factor was already present in an active form. It is concluded that "iRNA" may regulate protein synthesis, but without exhibiting specificity towards mRNAs, at least those tested so far.     

Increase of AKR-specific sequences in tumor tissues of leukemic AKR mice.

AKR mice produce, from shortly after birth, high titers of their endogenous Gross type murine leukemia virus, and develop a thymus-derived leukemia at 7-9 months of age. We show that this oncogenesis is accompanied by an increase in the number of AKR-specific DNA sequences in the tumor tissues, whereas the "non-target" organs are not affected. Sequence increase was determined by kinetic analysis of DNA reassociation using an AKR-murine leukemia virus (MuLV)-specific cDNA and also by hybridization with excess AKR cDNA. The AKR cDNA was selected to recognize AKR sequences without significant crossreaction with DNA sequences of other endogenous viruses. The results show that during the development of the leukemia, the number of AKR-MuLV-specific genes increases in tumor tissues by a factor of 1 1/2 to 2.     

History-Adjusted Marginal Structural Analysis of the Association between Hemoglobin Variability and Mortality among Chronic Hemodialysis Patients

Background and objectives: Hemoglobin variability is common among dialysis patients, and has been associated with increased mortality. The causal nature of this association has been difficult to ascertain because of potential time-dependent confounding, for which traditional statistical methods do not control.Design, settings, participants, & measurements: A retrospective cohort of 34,963 Fresenius Medical care dialysis patients from 1996 was assembled. Hemoglobin variability, absolute hemoglobin level, and temporal hemoglobin trend were measured over rolling 6-mo exposure windows. Their association with mortality was estimated using history-adjusted marginal structural analysis that adjusts for time-dependent confounding by applying weights to observations inversely related to the predictability of observed levels of hemoglobin.Results: In the primary analysis, each g/dl increase in hemoglobin variability was associated with an adjusted hazard ratio (HR) [95% confidence interval (CI)] for all-cause mortality of 1.93 (1.20 to 3.10). Neither higher absolute hemoglobin level nor increasing hemoglobin trend were significantly associated with mortality; adjusted HR (95% CI) 0.85 (0.64 to 1.11) and 0.60 (0.25 to 1.45), respectively.Conclusions: Marginal structural analysis demonstrates that hemoglobin variability is associated with increased mortality among chronic hemodialysis patients, and that this effect is more pronounced than appreciated using standard statistical techniques that do not take time-dependent confounding into account.Hemodialysis patients experience substantial changes in hemoglobin concentration over time (1–4). This variability derives both from patterns of care, such as changes in erythropoietin and intravenous iron dosing, as well as from comorbid conditions that either influence sensitivity to these therapies, or that directly affect red cell mass. Recently, we demonstrated an association between increased hemoglobin variability (Hgb-Var) and all-cause mortality among chronic dialysis patients (5).As is the case in all nonrandomized research, the observed association between Hgb-Var and death was subject to potential confounding. Confounding occurs when a variable (or variables) affects the likelihood of exposure (e.g. Hgb-Var) and of outcome (e.g. death), but does not serve as an intermediate between exposure and outcome. Standard methods of statistical adjustment are often sufficient to adjust for these confounders when they do not vary over time compared with their baseline values.Unfortunately, there are instances when application of standard statistical techniques may yield biased associations, such as in the presence of time-dependent confounding. Time-dependent confounders (TDC) are variables that have two different roles that are difficult to distinguish: (1) they influence subsequent exposure and outcome like confounders that are fixed over time, and (2) they also serve as intermediates (or links) between exposure and outcome. Although it is appropriate to adjust for their role as confounders, it is inappropriate to adjust for their role as intermediates on the causal pathway from exposure to outcome. If standard statistical techniques are used to adjust for TDC, they adjust for both roles simultaneously and, therefore, may underestimate true associations owing to the adjustment for the role as a causal pathway factor. For example, if Hgb-Var is both influenced by comorbid conditions and promotes these same conditions as part of the mechanism through which it causes poor clinical outcomes, simple adjustment for these comorbidities would lead to biased estimates of the Hgb-Var outcome relationship. Figure 1 serves to illustrate one potential TDC of the association between Hgb-Var and death, namely intravenous iron administration, which may independently be associated with Hgb-Var and mortality (Figure 1A), and may also serve on the causal pathway (Figure 1B).Open in a separate windowFigure 1.Example of the potential time-dependent confounding influence of intravenous iron on the association between hemoglobin variability (Hgb-Var) and death (A) when intravenous iron affects the degree of Hgb-Var and the likelihood of death and (B) also serves as an intermediate between Hgb-Var and death.The best means to avoid the possibility of time-dependent confounding is through randomization to fixed treatment protocols (9). Extending the prior example, this would mean randomizing subjects to high and low levels of Hgb-Var, and treating each group with equivalent amounts of intravenous iron. Unfortunately, current therapies do not enable randomization of subjects to varying degrees of Hgb-Var. Nonetheless, observational research can take advantage of newer statistical tools, such as history-adjusted marginal structural models (HA-MSM), which enable estimation of less biased measures of association from observational data in the presence of time-dependent confounding (8,10–11).Considering that the prior association may have been biased by the presence of time-dependent confounders, we have reanalyzed our data using HA-MSM to better estimate the causal association between Hgb-Var and mortality.     

Postappendectomy fluid collections in children: incidence, nature, and evolution evaluated using US

At the authors' medical center, most patients with postappendectomy fluid collections are treated conservatively. Thirty-two (15%) of 216 children underwent postoperative sonography following appendectomies. In ten patients (31%), a total of 16 fluid collections were found on the initial postoperative sonogram. In the seven patients (70%) whose fluid collections were confined to the pelvis, the condition was treated conservatively and it resolved in 2-9 weeks. In three patients, fluid collections required surgical drainage and proved to be abscesses. In two of the three patients, abscesses were multiple and widely distributed in the abdomen, and the patients were clinically ill. The authors conclude that clinically symptomatic fluid collections develop postoperatively in approximately 5% of children who have undergone appendectomy for acute appendicitis and that the size and course of the fluid collection can be objectively monitored using sonography. Such fluid collections confined to the pelvis ultimately resolve with conservative, nonoperative therapy, although resolution may take up to 2 months.     

Cellulitis due to Escherichia coli in three immunocompromised subjects

A case of severe photosensitivity in a girl with the Smith–Lemli–Opitz syndrome is reported. Children with this recessively inherited metabolic disorder of cholesterol metabolism present with a variety of congenital abnormalities of the nervous system and internal organs in association with varying degrees of mental retardation. Photosensitivity is a feature which has previously only briefly been mentioned in the literature in association with this syndrome. However, more recently, it has become apparent that photosensitivity is not uncommon among children with the Smith–Lemli–Opitz syndrome, although the nature of the photosensitivity in these patients has remained undefined. Our patient has suffered from sunlight intolerance since early infancy, with redness and pruritus of sun-exposed skin developing within minutes of sun exposure. Monochromator ultraviolet (UV) radiation and visible light testing revealed an immediate and persistent reaction to low-dose UVA at 350 nm, and an abnormal erythemal response to visible light at 400 nm.     

Uterus and endometrium: Regeneration processes in rabbit endometrium: a photodynamic therapy model

The origin and process of regeneration in rabbit endo metriumwas evaluated following photodynamic epithelial destructionusing topically applied anilnolevulinic acid (ALA). Selectivedestruction of endometrial epithelium was performed using photodynamictherapy (PDT). ALA was diluted to 200 mg/ml dextran 70 shortlyprior to adininistra tion. A volume of 1.2 ml was injected intothe left uterus. Intrauterine illumination (wavelength 630 nm,light dose 40–80 J/cm²was performed 3 h after drug administration.Tissue morphology was evaluated by light and scanning electronmicroscopy 1, 3, 7 and 28 days post-treatment (three animalsat each dine-point). Regeneration of the endometriwn followingepithelial ablation by PDT was fully activated after 24 h andwas completed after 72 h. Endometrial surface generation occurredby proliferation, originating primarily in deeper regions ofthe glands. Findings from our morphological follow-up studysupport the origin of endometrial regeneration being mainlyfrom undifferentiated stem cells and residual glandular epithelium.     

Comparison in the Same Patient of Aberrant Conduction and Bundle Branch Reentry After Dofetilide, a New Selective Class III Antiarrhythmic Agent

Dofetilide may induce aberrant intraventricular conduction due to its Class III effect. This report describes an atrial fibrillation patient in whom intraventricular conduction was studied before and after dofetilide using multiple endocardial recordings. Dofetilide provoked aberrant conduction during atrial fibrillation, and aberrancy could be mimicked with programmed atrial stimulation after restoration of sinus rhythm. However, during right ventricular slimulation, isolated bundle branch reentrant beats were recorded after induction of critical retrograde conduction delays. This occurred in the setting of relatively large differences in refractoriness between the right bundle branch and the right ventricular myocardium. This favored distal retrograde bundle branch block during ventricular extrastimulation, in turn enhancing bundle branch reentry. This potendal proarrhythmic mechanism deserves close attention in the further deveiopmeni of dofetilide and also of other new "pure" Class III agents.     

Photomedicine of the endometrium: experimental concepts

Gynaecological photomedicine offers new diagnostic and therapeuticmethods based on the interaction of light with the reproductiveorgans. One example is photodynamic therapy (PDT) in which photosensitizersare applied systemically or topically for selective endometrialablation. Several studies describing the potential use of PDTfor this application are reviewed. Basic experimental and clinicalaspects of PDT, such as photosensitizer types, application modes,irradiation parameters, optical properties of tissues and photodegradationof photosensitizers are discussed.