Biological properties of recombinant alpha-interferons: 40th anniversary of the discovery of interferons

IFNs were first described as potent antiviral agents 40 years ago, and recombinant IFN-alpha2a and IFN-alpha2b were approved for the treatment of hairy cell leukemia just 11 years ago. Today, alpha-IFNs are approved worldwide for the treatment of a variety of malignancies and virologic diseases. Although the exact mechanism of action of IFN-alpha in the treatment of such diseases is not fully understood, many advances have been made in the characterization of the physicochemical and diverse biological properties of this highly pleiotropic cytokine. Here we review recent developments in our understanding of the antiviral and immunoregulatory properties of IFN-alpha, the nature of the multisubunit IFN-alpha receptor, and the molecular mechanisms of signal transduction. Where available, we have included comparative data on recombinant alpha-IFNs derived from both naturally occurring and nonnaturally occurring synthetic genes. We also review clinical data and data on the side effects and antigenicity of different sources of recombinant alpha-IFNs in humans. These latter topics are of clinical interest, because they may potentially affect the efficacy of these various products. Hopefully, what is already known about IFN will prompt further exploration into the mechanism(s) of action of IFN-alpha and thus deliver new applications for this prototypic cytokine, whose full therapeutic potential is yet to be realized.     

Intraclass correlation estimates in a school-based smoking prevention study. Outcome and mediating variables, by sex and ethnicity

Most school-based smoking prevention studies employ designs in which schools or classrooms are assigned to different treatment conditions while observations are made on individual students. This design requires that the treatment effect be assessed against the between-school variance. However, the between-school variance is usually larger than the variance that would be obtained if students were individually randomized to different conditions. Consequently, the power of the test for a treatment effect is reduced, and it becomes difficult to detect important treatment effects. To assess the potential loss of power or to calculate appropriate sample sizes, investigators need good estimates of the intraclass correlations for the variables of interest. The authors calculated intraclass correlations for some common outcome variables in a school-based smoking prevention study, using a three-level model-i.e., students nested within classrooms and classrooms nested within schools. The authors present the intraclass correlation estimates for the entire data set, as well as separately by sex and ethnicity. They also illustrate the use of these estimates in the planning of future studies.     

S-phase fractions of breast carcinomas. Relationships to morphology, estrogen and progesterone receptors, and early recurrence

Analysis of the S-phase fractions (SPF) measured by in vitro thymidine labeling, morphological appearances, and estrogen receptor (ER) assays of primary invasive breast carcinomas demonstrated several interrelationships. Lobular, mucinous, tubular, and adenocystic carcinomas consistently had low SPF and were usually positive for ER. The same was true for the carcinomas of no special histologic type [the not otherwise specified (NOS) group of E. R. Fisher including "infiltrating ductal" and undifferentiated carcinomas] with minimal anaplasia. Medullary, atypical medullary, and morphologically unclassifiable carcinomas with marked nuclear anaplasia nearly always had high SPF and were usually negative for ER. High SPF was associated with advanced stages of carcinoma initially or with early recurrence following mastectomy.     

Predicting external sulphur requirement of alfalfa from sulphate sorption isotherm of Tanzanian soils

For Tanzanian soils dominant in hydrous oxides of iron and amorphous ferri-alumino silicate, a 48-hour (hr) mixing period with the sulphate (SO₄) solution was adequate for a near-equilibrium condition. Although differing in their SO₄ sorption capacity, all the soils sorbed SO₄ at or beyond 1µg ml^–1 sulphur (S) concentration in the supernatant. Hydroxyl (OH) ions were displaced during SO₄ sorption as indicated by a significant positive correlation between the amount of sorbed SO₄ and the difference in pH values determined in 0.1N K₂ SO₄ and 0.1N KCl, i.e. the dpH values.In a greenhouse experiment, alfalfa was grown on eight soils at six adjusted S concentrations. Sulphur deficiency symptoms appeared in the control pots of those soils which were low in native sorbed SO₄, SO₄ sorption capacity and initial soil solution S concentration. Sulphur fertilization increased dry matter (DM) yield as well as response to applied S. The external S concentration, i.e. adjusted S concentration required for 95% of the maximum DM yield, ranged from 0.8 to 8.2µg S ml^–1 with values less than 2.0 on most of the soils. The external S concentration decreased hyperbolically as the SO₄ sorption capacity of the soils increased. The total amount of fertilizer S required to obtain the external S concentration in solution, and at the same time satisfy the SO₄ sorption capacity of the soil at the external S concentration (determined from the sorption isotherm) was defined as the external S requirement for the specified yield level of alfalfa. The external S requirement for 95% of the maximum yield of alfalfa varied from soil to soil due to differences in their capacity and intensity for S nutrition.Part of a thesis by the senior author for the MSc (Agric) degree of the University of Dar es Salaam     

Monckeberg's calciphylaxis with necrosis of the glans penis: a case presentation

Monckeberg's calcific sclerosis of the media of the small-sized and medium-sized arteries is a well described and potentially life-threatening condition seen almost exclusively in patients with end-stage renal disease (ESRD) and with hyperparathyroidism. Penile gangrene resulting from this entity is associated with a mortality as high as 64%. A 65-year-old man with ESRD on dialysis for 6 years was referred to Harborview Medical Center with severe penile pain and partial necrosis of his glans penis, which progressed despite medical management. The patient had previously undergone amputations on all four extremities. After intraoperative biopsies of the proximal corpora cavernosa and spongiosum demonstrated viable tissue, he underwent partial penectomy. Pathologic evaluation revealed calciphylaxis within the media of the penile vessels. Two months later the patient had persistent wound-healing issues with intractable pain and thus underwent a complete penectomy with ultimate resolution of his severe pain.     

Expression of apolipoprotein(a) kringle IV type 9 in Escherichia coli: demonstration of a specific interaction between kringle IV type 9 and apolipoproteinB-100

A number of studies have provided evidence that lipoprotein(a) [Lp(a)] assembly is a two-step process in which initial non-covalent interactions between apolipoprotein(a) [apo(a)] and apolipoproteinB-100 (apoB-100) precede specific disulfide bond formation. We have designed a construct encoding apo(a) kringle IV type 9 (KIV9) in which the unpaired cysteine at position 67 in this kringle is replaced with a tyrosine. The single kringle was expressed in bacteria and purified to homogeneity from cell homogenates. The purified derivative (designated KIV9deltaCys) was assessed for its ability to bind to purified human LDL. This interaction was detected either by ELISA using immobilized LDL or by column chromatography in which LDL binding to KIV9deltaCys immobilized on Ni2+-Sepharose was determined. In both cases, the interaction of KIV9deltaCys and LDL was observed. Further, we demonstrated that the binding interaction was sensitive to the addition of amino acids including lysine, the lysine analogue epsilon- aminocaproic acid, arginine, phenylalanine and proline, with arginine and lysine having the greatest inhibitory effect. Binding of KIV9deltaCys to an immobilized apoB peptide spanning residues 3732-3745 of apoB was also demonstrated by ELISA. As was the case for LDL, this binding interaction was sensitive to the addition of arginine and lysine. Computer modeling of KIV9 demonstrated an excellent fit with residues 3732-3738 (PSCKLDF) of the apoB peptide. The modeling predicts the presence of overlapping lysine and phenylalanine-binding pockets in KIV9 which explains the inhibitory effects of lysine, arginine and phenylalanine which were observed in the binding assays. In summary, this study represents the first demonstration that KIV9 can interact directly with LDL through non-covalent interactions which may contribute to the first step of Lp(a) formation.      

Indicators for inspection and maintenance planning of concrete structures

Based on an idea introduced by Benjamin and Cornell (1970. Probability, statistics and decision for civil engineers. New York: McGaw Hill) and previous works by the authors it is demonstrated how condition indicators may be formulated for the general purpose of quality control and for assessment and inspection planning in particular. The formulation facilitates quality control based on sampling of indirect information about the condition of the considered components. This allows for a Bayesian formulation of the indicators whereby the experience and expertise of the inspection personnel may be fully utilized and consistently updated as frequentistic information is collected. The approach is illustrated on an example considering a concrete structure subject to corrosion. It is shown how half-cell potential measurements may be utilized to update the probability of excessive repair after 50 years. Furthermore in the same example it is shown how the concept of condition indicators might be applied to develop a cost optimal maintenance strategy composed of preventive and corrective repair measures.     

Endothelial injury following experimental subarachnoid hemorrhage in rats: effects on brain blood flow

BACKGROUND: The leading cause of death and disability in patients suffering from aneurysmal subarachnoid hemorrhage (SAH) is cerebral vasospasm, a persistent, progressive, and often irreversible constriction of cerebral arteries. A wide array of pathological changes occur in cerebral arteries following SAH, with endothelial injury being the earliest and most consistent one. Since intact endothelium modulates many reflexes that influence vascular tone, damage to them may represent a significant contributor to cerebral vasospasm. METHODS: Changes in local cerebellar blood flow (LCBF) and pathological alterations in major cerebral arteries were studied and compared in rats at various time intervals following SAH. SAH induced by the subarachnoid injection of 0.3 ml of whole blood. Sham rats received a subarachnoid injection of 0.3 ml of isotonic saline. RESULTS: Except for an immediate but transient decrease, LCBF remained unchanged over a 3 day period following saline injection. Likewise, there were no pathological alterations in cerebral arteries of saline-injected rats. In contrast, the subarachnoid injection of whole blood produced significant changes in both LCBF and cerebral arteries. Within 30 minutes post-blood injection, LCBF became significantly decreased and remained so for 4 hours. However, within 24 hours, LCBF had returned to control levels where it remained for 3 days. Endothelial injury was observed in the basilar and middle cerebral arteries from 30 minutes through 4 hours, the same periods in which LCBF was significantly reduced. Within 24 hours, the time period in which LCBF had rebounded to control ranges, cerebral arteries showed no evidence of endothelial damage and resembled control cells. CONCLUSION: The results indicate a direct correlation between changes in LCBF and the structural integrity of endothelial cells in the early stages following SAH. The lack of chronically depressed LCBF (after 1 day) may be related to the quick structural repair of endothelium.