Induction of oral cavity tumors in F344 rats by tobacco-specific nitrosamines and snuff

The tumorigenic activities toward the oral cavity of snuff, its extracts, and two of its major nitrosamines, N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were evaluated in male F344 rats. In one protocol, groups of 21-30 rats were treated beginning at age 10 weeks by chronic application to the oral cavity for 131 weeks of either H2O, an H2O extract of snuff, an H2O extract of snuff enriched with ten times its indigenous concentration of NNN and NNK, or with NNN and NNK in H2O. The incidence of oral cavity tumors in the rats treated with NNN and NNK was 8 of 30, compared to 0 of 30 in controls (P less than 0.05). These results demonstrate that NNN and NNK can induce tumors locally in the oral cavity of F344 rats. Oral cavity tumors were also observed in 3 of 30 rats treated with snuff extract enriched with NNN and NNK, but not in the rats treated with snuff extract alone. In a second protocol, a test canal was surgically created in the lower lip of groups of 21-32 rats, and either snuff, H2O-extracted snuff, or snuff enriched with its own H2O extract was inserted in the test canal 5 times weekly for 116 weeks. A group of 10 control rats had surgery only. Among the 32 rats treated with snuff, 3 had oral cavity tumors; one was a squamous cell carcinoma originating in the test canal and invading the gingiva, one was a papilloma of the test canal, and one was a papilloma of the hard palate. Oral cavity tumors were also observed in 2 of 21 rats treated with H2O-extracted snuff and 1 of 32 rats treated with snuff enriched with its H2O extract. Oral tumors were not observed in control rats. The results of this study indicate that snuff and individual nitrosamines present in snuff can induce oral cavity tumors in F344 rats and support the epidemiological observations which indicate that snuff dipping causes oral cancer in man.     

The Development and Teaching of the Ethical Principles and Guidelines for Family Scientists*

This article describes the development of the Ethical Principles and Guidelines for Family Scientists that the National Council on Family Relations Board of Directors unanimously approved. Furthermore, it discusses the importance of ethics education for family professionals and provides suggestions for educators. Finally, the ethical principles and guidelines are delineated. We argue that the development of a scholarship on ethics education is important for current and future family scientists.     

On the measurement of susceptibility in epidemiologic studies

Although relative effects of risk factors (relative risks) are commonly used in epidemiologic studies of disease, these measures do not provide estimates of the proportion of persons who are "susceptible" to the risk factor. Susceptibility may be defined under a simple sufficient cause model as the underlying factor (or set of factors) sufficient to make a person contract a disease following exposure. The authors derive simple estimates of the proportion of susceptibles in a population based on relative risk, and disease and exposure frequencies. The proportion of susceptibles increases with increasing disease frequency and relative risk but declines at high exposure frequency. For many chronic diseases with a lifetime risk in the range of 1-10 per cent, rare exposures suggest the presence of a large proportion of susceptibles, whereas common exposures suggest fewer susceptibles in the population. The estimation of the proportion of susceptibles is important in the search for genetic and environmental factors that interact with measured risk factors in etiologic studies of disease.     

Evidence for a neural basis of age-related visual field loss in normal observers

Many studies have reported a decrease in visual field sensitivity as a function of increasing age in normal individuals. This age-related sensitivity loss has mainly been attributed to reductions in pupil size and transmission losses of the ocular media (particularly the lens), although neural losses in the retina, optic nerve and visual cortex have also been suggested. We evaluated the role of preretinal factors on normal visual field changes associated with aging. The central visual field of both eyes of 62 normal subjects (ages 20 to 72) were evaluated with Program 30-2 of a modified Humphrey Field Analyzer. Three test procedures were employed: (1) a standard visual field evaluation; (2) a yellow target on a yellow background condition (530 nm cutoff filter) to minimize the influence of lens transmission losses with age; and (3) a large target/high background luminance "yellow on yellow" test condition (530 nm cutoff filter, 635 asb background, Size V target) to minimize both pupil size and lens effects on central visual field sensitivity. In addition, relative lens absorption estimates were obtained for each subject. All three test conditions revealed a loss in visual field sensitivity with increasing age (approximately 0.8 dB per decade) but no meaningful differences were found among the three test procedures. Relative lens density increased with age but was not related to visual field sensitivity for any of the three test conditions. These data suggest that normal age-related visual field sensitivity changes are primarily due to neural losses rather than preretinal factors.     

LSECtin interacts with filovirus glycoproteins and the spike protein of SARS coronavirus

Cellular attachment factors like the C-type lectins DC-SIGN and DC-SIGNR (collectively referred to as DC-SIGN/R) can augment viral infection and might promote viral dissemination in and between hosts. The lectin LSECtin is encoded in the same chromosomal locus as DC-SIGN/R and is coexpressed with DC-SIGNR on sinusoidal endothelial cells in liver and lymphnodes. Here, we show that LSECtin enhances infection driven by filovirus glycoproteins (GP) and the S protein of SARS coronavirus, but does not interact with human immunodeficiency virus type-1 and hepatitis C virus envelope proteins. Ligand binding to LSECtin was inhibited by EGTA but not by mannan, suggesting that LSECtin unlike DC-SIGN/R does not recognize high-mannose glycans on viral GPs. Finally, we demonstrate that LSECtin is N-linked glycosylated and that glycosylation is required for cell surface expression. In summary, we identified LSECtin as an attachment factor that in conjunction with DC-SIGNR might concentrate viral pathogens in liver and lymph nodes.     

Ventromedial tegmental lesions abolish offense without disturbing predation or defense

Offense, defense, and predation, three kinds of aggressive behavior, are differentially affected by lesions of the ventromedial tegmentum of the brainstem of the rat. The lesions abolish offense while leaving defense and predation undisturbed. The offense behavior against another strange male, including bite-and-kick attack, offensive sideways posture, and offensive upright posture, was totally abolished, while the rats showed intact motor patterns of defensive upright posture, chasing, and killing bite in the tests for defense and predation. It is argued that these results support a motivational systems analysis of mammalian aggressive behavior. According to such an analysis, offense, defense, and predation are controlled by discrete motivational mechanisms located in different brainstem regions.     

Proposed methods for the measurement of regional renal blood flow using heat transfer analysis

The kidney, with its heterogeneous regional perfusion in the two anatomically and functionally distinct vascular beds of the renal cortex and medulla, and with its nonuniform blood vessel geometries, presents a unique challenge for measuring intrarenal blood flow distribution. Determining whole organ perfusion, on the other hand, is comparatively simple for the kidney, but it provides relatively little information about the suspected dependency of renal excretory function on local perfusion rate. Among the variety of methods proposed for gauging regional renal blood flow, some depend on measuring one or more of the tissue's thermal properties. The most straightforward, but least reliable, involve measurements either of focal tissue temperature alone, or of regional tissue thermal gradients. Simply using heat as a diffusible indicator, however, is unreliable as a measure of blood flow, for many of the same reasons that using an inert gas in a dilution technique is unreliable. Recently developed thermal analytical methods, though, hold promise for measuring local tissue blood flow with accuracy and precision. Two of them are reviewed here. One depends on measurement of the effective thermal conductivity of a small mass of tissue by evaluating the steady state ratio between regional unidirectional heat flux across it and the associated temperature gradient in one vector along a segment of it through an imposed spheroidal heat field. The other depends on analyses of tissue temperature decay subsequent to a controlled pulse of heat delivered through a small inserted thermistor bead. Both techniques use bioheat transfer equations to deduce regional blood flow Research by K.R. Holmes and M.M. Chen was supproted by NIH-NHLBI Grant HL27011, that by T. Adams and S.R. Heisey through the Michigan Heart Association, and that by W.S. Spielman through a grant from the NSF (PCM 8110588) who is a recipient of NIH Research Career Development Award HL01010.     

Structure of an autoimmune T cell receptor complexed with class II peptide-MHC: insights into MHC bias and antigen specificity

T cell receptor crossreactivity with different peptide ligands and biased recognition of MHC are coupled features of antigen recognition that are necessary for the T cell's diverse functional repertoire. In the crystal structure between an autoreactive, EAE T cell clone 172.10 and myelin basic protein (1-11) presented by class II MHC I-Au, recognition of the MHC is dominated by the Vbeta domain of the TCR, which interacts with the MHC alpha chain in a manner suggestive of a germline-encoded TCR/MHC "anchor point." Strikingly, there are few specific contacts between the TCR CDR3 loops and the MBP peptide. We also find that over 1,000,000 different peptides derived from combinatorial libraries can activate 172.10, yet the TCR strongly prefers the native MBP contact residues. We suggest that while TCR scanning of pMHC may be degenerate due to the TCR germline bias for MHC, recognition of structurally distinct agonist peptides is not indicative of TCR promiscuity, but rather highly specific alternative solutions to TCR engagement.     

Crosslink formation in porcine valves stabilized by dye-mediated photooxidation

Bovine pericardial and porcine valve materials stabilized by dye-mediated photooxidation have shown potential for bioprosthetic valve use. Previously, in vitro and in vivo stability of these materials was demonstrated through enzymatic, chemical, extraction, rat subcutaneous, and functional challenges. Here, we examine the stability of photooxidized porcine aortic valves through amino acid, crosslink, and hydrothermal isometric tension analysis. Photooxidation reduced intact histidine residues from 17.0 to 0 residues per 1000, indicating the photooxidative alteration of this amino acid. Diphenyl borinic acid-derivitized hydrolyzates of proteins were separated by high-performance liquid chromatography, which identified several amino acid crosslinks that appeared with photooxidation that were absent in untreated controls. Thermal relaxation analysis indicated a significantly higher (p < 0.0002) thermal stability for photooxidized porcine cusps than that of untreated controls, with mean relaxation times for untreated cusps of 14,000 +/- 4650 versus 22,900 +/- 2480 s for photooxidized cusps. In summary, porcine aortic valve tissue treated by dye-mediated photooxidation contains new chemical species and exhibits properties consistent with intermolecular crosslink formation, which explain the increased biostability of this material and its potential for use in bioprosthetic devices.