Combining morphological characteristics and DNA barcoding techniques confirm sea urchins of the genus Echinometra (Echinodermata: Echinoidea) in marine habitat located at extreme regions of the Caribbean Sea.

Echinometra spp. are pantropical echinoids found in benthic marine habitat throughout the Caribbean, Atlantic, and Indo-West Pacific oceanic regions. Currently, morphology and molecular data is sparse for echinoids observed along the northeastern coast of Toco, Trinidad where they are relatively common. Additionally, accurate species identity for Echinometra spp. remains dynamic at both northernmost and southernmost parts of the Caribbean Sea. Although distribution of sea urchins in the genus Echinometra have extensively been studied throughout the Atlantic and Indo-West Pacific, information on its range of distribution at the edge of the Caribbean Sea is lacking. In this study, the mitochondrial Cytochrome c Oxidase subunit I (mt COI) gene was amplified using polymerase chain reaction, then sequenced. Based on successfully obtained gene sequences for 581 base pairs, the echinoid species E. lucunter and E. viridis were identified for black and red color morphotypes from Trinidad (n = 23) and Key Largo, Florida (n = 6) respectively. Furthermore, these specimens were genetically identical to species identified in other studies for Puerto Rico, Panamá, Honduras, and Belize. Although morphological variations, such as spine and test color occur throughout Echinometra spp., molecular identification using the barcoding technique confirmed E. lucunter color morphs for the first time in Trinidad. Since the status of E. lucunter populations, specifically at the most northern and southern regions of the Caribbean Sea is dynamic, further studies using gene markers are essential in determining species distribution, in light of current trends in climate change.

World Trade Organization disputes related to animal diseases.

Four trade disputes concerning animal diseases have undergone the formal dispute resolution procedure of the World Trade Organization (WTO). These cases clarify a number of provisions of the Agreement on the Application of Sanitary and Phytosanitary Measures (SPS Agreement). A national measure that contradicts a standard set by the World Organisation for Animal Health (OIE), for example by prohibiting a product that is permitted under the OIE standard, is not 'based on' that standard. Such a measure must be based on an appropriate risk assessment. For animal diseases, this means not only assessing the likelihood of entry, establishment or spread of the disease, and the associated biological and economic consequences, but also assessing each feasible mitigation measure. Any mitigation measure imposed must be rationally supported by the risk assessment. A highly trade-restrictive measure, such as a ban, is more easily justified if the identified risk is high. A measure imposed to protect health cannot impose stricter requirements on one product than on another with a similar level of risk. A WTO Member acts inconsistently with the SPS Agreement if an alternative measure, which is technically and economically feasible and restricts trade less, would achieve the desired level of protection. Countries must adapt their SPS requirements to reflect the disease risk of the area or zone from which a product comes and for which it is destined. Procedures to assess risk and determine the disease status of a region must be completed without unjustified delays, and only the information necessary for this can be requested of the exporter.

Quatre différends commerciaux en lien avec des maladies animales ont été soumis à l'Organisation mondiale du commerce (OMC) en vue de déclencher la procédure formelle de règlement des différends. Ces cas ont permis de clarifier un certain nombre de dispositions de l'Accord sur l'application des mesures sanitaires et phytosanitaires (Accord SPS). Ainsi, une mesure nationale contredisant une norme établie par l'Organisation mondiale de la santé animale (OIE), par exemple en interdisant un produit que ladite norme de l'OIE autorise, ne peut en aucun cas se prévaloir d'être « basée sur ¼ cette norme. Les mesures de ce type doivent se fonder sur une évaluation appropriée du risque. S'agissant des maladies animales, cela signifie qu'il faut non seulement évaluer les probabilités d'entrée, d'établissement ou de dissémination de l'agent causal de la maladie en question, ainsi que les conséquences biologiques et économiques qui en résultent, mais aussi évaluer une par une les différentes mesures d'atténuation réalisables. Toute mesure d'atténuation imposée doit être fondée de manière rationnelle sur cette évaluation du risque. Les mesures fortement restrictives, par exemple les interdictions, sont d'autant plus faciles à justifier que le risque identifié est élevé. Une mesure appliquée pour un produit déterminé dans le but de protéger la santé ne peut pas imposer de conditions plus strictes que celles portant sur d'autres produits présentant un niveau de risque similaire. Un membre de l'OMC agirait de manière incompatible avec l'Accord SPS s'il existe une mesure alternative, techniquement et économiquement réalisable mais moins contraignante pour le commerce, qui permettrait d'atteindre le niveau de protection requis. Les pays doivent adapter leurs exigences sanitaires et phytosanitaires en fonction du risque de maladie dans les régions ou zones de provenance et de destination du produit. Les procédures visant à évaluer le risque et à déterminer le statut d'une région au regard d'une maladie déterminée doivent être menées à terme sans délai injustifié et elles constituent le seul objet des informations exigibles auprès du pays exportateur.

El procedimiento oficial de solución de controversias de la Organización Mundial del Comercio (OMC) ha sido aplicado a cuatro litigios comerciales relacionados con enfermedades animales. Estos casos han resultado esclarecedores por lo que respecta a algunas de las disposiciones del Acuerdo sobre la Aplicación de Medidas Sanitarias y Fitosanitarias (Acuerdo MSF). Si una medida nacional contraviene una norma dictada por la Organización Mundial de Sanidad Animal (OIE), por ejemplo porque prohíbe un producto que según esa norma debe estar permitido, no se considera que tal medida está «basada en¼ la norma en cuestión. Semejante medida debe reposar en una adecuada determinación del riesgo. En el caso de las enfermedades animales, ello supone no solo determinar la probabilidad de penetración, establecimiento o propagación de la patología, así como sus posibles repercusiones biológicas y económicas, sino también evaluar cada una de las medidas factibles de mitigación. Toda medida de mitigación que se imponga debe ser una consecuencia racional del proceso de determinación del riesgo. Una medida que sea muy restrictiva del comercio, como pueda ser una prohibición, se justificará más fácilmente cuando se haya determinado previamente que existe un gran riesgo. Una medida destinada a proteger la salud no puede imponer a un producto requisitos más estrictos que a otro que entrañe un nivel parecido de riesgo. Un Miembro de la OMC no estará respetando el Acuerdo MSF cuando exista una medida alternativa, que sea técnica y económicamente factible y restrinja en menor medida el comercio, con la que se pueda lograr el nivel deseado de protección. Los países deben adaptar sus requisitos sanitarios y fitosanitarios al riesgo de enfermedad reinante en la zona de origen y la zona de destino del producto en cuestión. Los procedimientos para evaluar el nivel de riesgo de una región y determinar la situación de una enfermedad en ella deben ser aplicados sin demoras injustificadas y solo cabe pedir al exportador la información que sea necesaria para llevar a cabo este proceso.

Effects of aerobic exercise training on cognitive function and cortical vascularity in monkeys.

This study examined whether regular exercise training, at a level that would be recommended for middle-aged people interested in improving fitness could lead to improved cognitive performance and increased blood flow to the brain in another primate species. Adult female cynomolgus monkeys were trained to run on treadmills for 1 h a day, 5 days a week, for a 5 month period (n=16; 1.9+/-0.4 miles/day). A sedentary control group sat daily on immobile treadmills (n=8). Half of the runners had an additional sedentary period for 3 months at the end of the exercise period (n=8). In all groups, half of the monkeys were middle-aged (10-12 years old) and half were more mature (15-17 years old). Starting the fifth week of exercise training, monkeys underwent cognitive testing using the Wisconsin General Testing Apparatus (WGTA). Regardless of age, the exercising group learned to use the WGTA significantly faster (4.6+/-3.4 days) compared to controls (8.3+/-4.8 days; P=0.05). At the end of 5 months of running monkeys showed increased fitness, and the vascular volume fraction in the motor cortex in mature adult running monkeys was increased significantly compared to controls (P=0.029). However, increased vascular volume did not remain apparent after a 3-month sedentary period. These findings indicate that the level of exercise associated with improved fitness in middle-aged humans is sufficient to increase both the rate of learning and blood flow to the cerebral cortex, at least during the period of regular exercise.

Colostrinin-driven neurite outgrowth requires p53 activation in PC12 cells.

1. Colostrinin (CLN) induces maturation and differentiation of murine thymocytes, promotes proliferation of peripheral blood leukocytes, induces immunomodulator cytokines, and ameliorates oxidative stress-mediated activation of c-Jun NH2-terminal kinases. 2. Here we report that upon treatment with CLN, medullary pheochromocytoma (PC12) cells ceased to proliferate and extend neurites. 3. The arrest of CLN-treated PC12 cells in the G1 phase of the cell cycle was due to an increase in the phosphorylation of p53 at serine(15) (p53ser15) and expression of p21WAF1. PC12 cells treated with inhibitory oligonucleotides to p53 lacked p53ser15 and p21WAF1 expression, and did not show morphological changes after CLN exposure. Transfection with inhibitory oligonucleotides to p21WAF1 had no effect on p53 activation; however, cells failed to arrest or extend neurites. An oligonucleotide inhibiting luciferase expression had no effect on CLN-mediated p53 activation, p21WAF1 expression, growth arrest, or neurite outgrowth. 4. We conclude that CLN induces delicate cassettes of signaling pathways common to cell proliferation and differentiation, and mediates activities that are similar to those of hormones and neurotrophins, leading to neurite outgrowth.

Modulation of 4HNE-mediated signaling by proline-rich peptides from ovine colostrum.

In previous studies we showed that colostrinin (CLN), a complex of proline-rich polypeptides derived from ovine colostrum, induces mitogenic stimulation, as well as a variety of cytokines in human peripheral blood leukocytes, and possesses antioxidant activity in pheochromocytoma (PC12) cells. In this study we investigated the effects of CLN on 4-hydroxynonenal (4HNE)-mediated adduct formation, generation of reactive oxygen species (ROS), glutathione (GSH) metabolism, and the modification of signal transduction cascade that leads to activation of c-Jun N-terminal kinase (JNK) in PC12 cells. Here we demonstrate that CLN (1) reduced the abundance of 4HNE-protein adducts, as shown by fluorescent microscopy and Western blot analysis; (2) reduced intracellular levels of ROS, as shown by a decrease in 2',7'-dichlorodihydro-fluorescein-mediated fluorescence; (3) inhibited 4HNE-mediated GSH depletion, as determined fluorimetrically; and (4) inhibited 4HNE-induced activation of JNKs. Together, these findings suggest that CLN appears to down-regulate 4HNE-mediated lipid peroxidation and its product-induced signaling that otherwise may lead to pathological changes at the cellular and organ level. These findings also suggest further that CLN could be useful in the treatment of diseases such as Alzheimer's, as well as those in which ROS are implicated in pathogenesis.

Organization of cerebellar and area "y" projections to the nucleus reticularis tegmenti pontis in macaque monkeys.

Axonal projections to the nucleus reticularis tegmenti pontis (RTP) were studied in 11 macaque monkeys by mapping axonal degeneration from lesions centered in the dentate and interpositus anterior (IA) nuclei and by mapping anterograde transport of tritiated amino acid precursors injected into the dentate nucleus. Projections from the dentate and IA nuclei overlap in central parts of the body of RTP, but the terminal field of dentate axons extends dorsomedial and rostral to the terminal field of IA axons, and IA terminal fields extend more ventrolaterally. A caudal to rostral topography of projections from each nucleus onto dorsal to ventral parts of RTP was seen. Projections from rostral parts of both nuclei terminate in a sublemniscal part of the nucleus. The topography of dentate and IA projections onto central to ventrolateral RTP appears to match somatotopic maps of these cerebellar nuclei with the somatotopic map of projections to RTP from primary motor cortex. Projections from caudal and ventral parts of the dentate nucleus appear to overlap oculomotor inputs to rostral, dorsal, and medial RTP from the frontal and supplementary eye fields, the superior colliculus, and the oculomotor region of the caudal fastigial nucleus. Projections to the paramedian part of RTP from vestibular area "y" were also found in two cases that correlated with projections to vertical oculomotor motoneurons. The maps of dentate and IA projections onto RTP correlate predictably with maps of dentate and IA projections to the ventrolateral thalamus and subnuclei of the red nucleus that were made from these same cases (Stanton [1980b] J. Comp. Neurol. 192:377-385).

Enhanced in vivo sensitivity of in vitro interferon-treated B16 melanoma cells to CD8 cells and activated macrophages.

Mouse B16 melanoma cells maintained in vitro in the presence of interferon (IFN)-alpha become resistant to the in vitro antiproliferative effects of IFN-alpha. However, IFN-alpha-treated mice inoculated with these in vitro IFN-treated cells (B16 alpha res cells) have significantly increased life spans (ILS) and significantly higher cure rates than IFN-alpha-treated mice inoculated with B16 cells. This unexpectedly greater sensitivity of B16 alpha res cells to the in vivo antitumor effects of IFN-alpha was evaluated by in vivo cell depletion experiments. Depletion of either activated peritoneal macrophages or cytotoxic T lymphocytes (CTL) reduced the ILS of IFN-treated B16 alpha res-inoculated mice to a level comparable to that of IFN-treated B16-inoculated mice. Depletion of natural killer (NK) cells did not affect the ILS for IFN-treated B16 alpha res-inoculated mice. These studies indicate that activated macrophage and CD8 cell function, but not NK cell function, is important for the enhanced antitumor effects induced by IFN-alpha against B16 alpha res cells. Macrophage killing was unlikely to be mediated by TNF-alpha or IL-1 as B16 and B16 alpha res cells were equally sensitive to TNF-alpha and insensitive to IL-1 in vitro. Further, H-2K antigen expression is significantly more readily inducible on B16 alpha res cells than on B16 cells, consistent with enhanced CD8-mediated killing due to increased MHC class I antigen expression.

Production of interferon gamma messenger RNA by cells of non-immune origin.

There is general agreement that IFN-gamma is produced only by cells of immune origin (T-cells, NK cells, and recently macrophages). However, indirect evidence has suggested that undetectable, low levels of IFN-gamma produced by cells of non-immune lineage, such as the murine line L-929, enhanced the antiviral activity of IFNs-alpha and/or beta following induction by agents such as the double stranded RNA poly ICLC. Since L-929 cells were one of the prototypic cell lines for studying murine IFN induction and action, we felt that it would be important to validate this observation by detection of the mRNA for IFN-gamma. If confirmed, it might indicate a role for IFN-gamma in non-immune cells. The present investigations revealed that mouse L-929 fibroblasts produce IFN-gamma message following exposure to conventional IFN-alpha/beta inducers such as poly ICLC or Newcastle disease virus. In addition, we found that IFN-gamma itself will induce its own message. We further show that this is not a phenomenon isolated to transformed cells since we found that normal mouse embryo fibroblasts also produced the message, however in a constitutive fashion.

Modulation of immune responses by anabolic androgenic steroids.

Anabolic androgenic steroids (AS) have recently been placed on the Food and Drug Administration's (FDA's) list of controlled substances, because of the adverse effects seen in athletes taking accelerated dosages in attempts to enhance performance. Reported deleterious effects on abusers include sterility, gynecomastia in males, acne, balding, psychological changes, and increased risks of heart disease and liver neoplasia. Considering the roles of the immune and neuroendocrine systems and their interactions in many of these pathologies, it is important to determine the effects of these derivitized androgens on this connection. Little is known in this respect. We therefore determined the effects of anabolic steroids on certain immune responses and their effects on the extrapituitary production of corticotropin by lymphocytes. We present evidence that (1) both 17-beta and 17-alpha esterified AS, nandrolone decanoate and oxymethenelone, respectively, significantly inhibited production of antibody to sheep red blood cells in a murine abuse model; (2) the control androgens testosterone and dehydroepian-drosterone (DHEA) or sesame seed oil vehicle had no significant effects on antibody production; (3) nandrolone decanoate and oxymethenelone directly induced the production of the inflammatory cytokines IL-1 beta and TNF-alpha from human peripheral blood lymphocytes but had no effect on IL-2 or IL-10 production; (4) control androgens had no direct cytokine inducing effect; (5) nandrolone decanoate significantly inhibited IFN production in human WISH and murine L-929 cells; and (6) nandrolone decanoate significantly inhibited the production of corticotropin in human peripheral blood lymphocytes following viral infection. These data indicate that high doses of anabolic steroids can have significant effects on immune responses and extrapituitary production of corticotropin. Furthermore, the mouse model should provide an effective means by which to study other deleterious effects of anabolic steroid abuse in humans.

Topography of projections to posterior cortical areas from the macaque frontal eye fields.

Frontal eye field (FEF) projections to posterior cortical areas were mapped by autoradiography of tritiated amino acids (Leu, Pro) in six macaque monkeys. In three monkeys, the large saccade part of the FEF (IFEF) was identified by microstimulation and injected with tracers. In a fourth monkey, the small saccade part of the FEF (sFEF) was identified by microstimulation and injected with tracer. Tracer injections were placed into the sFEF region of two other monkeys using anatomical landmarks. The IFEF and sFEF generally had distinct and largely segregated projections to posterior cortical areas, and the overall pattern of labeling in visual areas with established topology indicates that IFEF neurons preferentially project to areas having large and eccentric receptive fields, whereas sFEF neurons project to areas having smaller, more centrally located fields. The terminal fields from the sFEF were more widespread than those from IFEF. Projections from sFEF terminated in the lateral intraparietal area (LIP), the ventral intraparietal area (VIP), and the parietal part of visual area V3A, in the fundus of the superior temporal visual area (FST), the middle temporal area (MT), the medial superior temporal area (MST), the temporal part of visual area V4, the inferior temporal area (IT), and the temporal-occipital area (TEO) and in occipital visual areas V2, V3, and V4. Projections from IFEF terminated in parietal areas 7a, LIP, and VIP and the medial part of parietal area PE; in temporal areas MST and the superior temporal polysensory area (STP); and in occipital area V2 and posterior cingulate area 23b. Projections from IFEF and sFEF appeared to terminate in different parts of common target areas in MST, LIP, and V2. The topography of IFEF and sFEF projections to LIP suggests that this posterior eye field may also be organized by saccade amplitude. Most terminal labeling from FEF injections was bilaminar to layers I and V/VI, but labeling in area LIP, area MT, the medial part of area PE, and area 23b was columnar-form to all layers.

Enhanced in vivo sensitivity to interferon with in vitro resistant B16 tumor cells in mice.

Mouse B16 melanoma cells rapidly develop resistance to the antiproliferative effects of interferon alpha (IFN alpha) and interferon beta (IFN beta) when they are exposed to the interferons in vitro. This resistance was characterized to be non-genetic and dose-dependent, and does not alter other IFN-induced effects such as antiviral effects and elevation of 2',5'-oligoadenylate synthetase activity in IFN-treated cells. The study of these IFN-resistant cells has been extended to an in vivo tumor model. Resistance, if it occurred in vivo, did not adversely affect the survival of IFN-treated mice. Further, IFN-treated mice inoculated with B16 cells that were resistant in vitro (B16 alpha res cells) survived significantly longer than IFN-treated mice inoculated with B16 cells that were sensitive in vitro. The IFN-treated B16 alpha res-inoculated mice had a significantly higher cure rate as well. The prolonged survival of the mice bearing B16 alpha res cell tumors did not seem to be caused by the slower growth rate of the B16 alpha res cells, since experiments performed with a tenfold higher B16 alpha res cell inoculum and a tenfold lower B16 cell inoculum did not show any change in the survival pattern. It is clear that in vitro resistant B16 alpha res cells are more sensitive to antitumor effects induced by IFN in vivo than in vitro sensitive B16 cells.

A three-dimensional reconstruction of the human hypothalamus.

A previous three-dimensional reconstruction of the rat hypothalamus revealed an organization of nuclei into three major clusters. This clustering may relate to the presence of three hypothalamic anlagen in the embryo and to a restriction of marker proteins and transcription factors to specific regions of the hypothalamus during development. To see if a similar clustering was apparent in the human hypothalamus, a reconstruction of the hypothalamus from a male cadaver was prepared. The reconstruction showed a clustering of nuclei into three anterior-posterior groups. With reference to the well-defined human supraoptic nucleus, the suprachiasmatic and lateral mammillary nuclei were proportionately smaller in this single human specimen than would be expected from data in the rat. A high degree of homology between hypothalamic structures in the rat and human were generally observed.

Thalamic afferents of area 4 and 6 in the dog: a multiple retrograde fluorescent dye study.

In the present study, we compared the distribution of thalamocortical afferents of cortical area 4 to that of cortical area 6 in the dog, using fluorescent tracers. Multiple injections of combinations of two dyes (diamidino yellow dihydrochloride, Evans blue, fast blue, granular blue) were made into either the anterior and posterior sigmoid gyri or into the medial and lateral regions of the anterior sigmoid gyrus in the anesthetized dog. We found that the thalamic afferents of areas 4 and 6 arise from topographically organized bands of cells that traverse several thalamic nuclei and extend throughout the rostrocaudal extent of the thalamus. The most medial band included area 6-projecting neurons in the anterior nuclei, the rhomboid nucleus, the ventral anterior nucleus (VA), ventromedial nucleus (VM) and mediodorsal nucleus (MD). Within this band, cells projecting to medial area 6 a alpha tended to be more numerous in the anterior nuclei, anterior parts of VA and VM and anterior and caudal parts of MD. Fewer cells in MD but more cells in caudal parts of VA and VM projected to lateral area 6 a beta. Lateral bands of cells in central through lateral parts of VA and VL projected topographically to lateral area 4 on the anterior sigmoid gyrus and lateral through medial parts of postcruciate area 4. The most lateral band of cells in VL continued ventrally into the zona incerta. Area 4 also received input from VM and the central lateral (CL) and centrum medianum (CM) nuclei.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell-cell communication correlates with pattern formation in molting Manduca midgut epithelium.

The midgut epithelium of larval Manduca sexta is constructed of single goblet cells surrounded by a one-cell-thick reticulum of columnar cells. This pattern is expanded at each molt by the addition of new cells. Between molts, these epithelial cells are not dye coupled, even though gap junctions are present. Proliferating stem cells are dye coupled in small groups early in the molt. Then, at mid-molt, the whole epithelium temporarily becomes dye coupled. This is when the new (expanded) pattern is being established. Later, at the end of the molt, the epithelium returns to the non-coupled state. These results suggest that cell communication via gap junctions may play a role in cell patterning.

Topography of projections to the frontal lobe from the macaque frontal eye fields.

Efferents from the frontal eye fields (FEF) to the ipsilateral frontal lobe were studied by autoradiography of tritiated tracers (leucine, proline, and fucose) in seven macaque monkeys that were used previously to describe subcortical connections. In four of the cases, tracer injection sites were confirmed by low thresholds for the electrical elicitation of saccadic eye movements. Cases were grouped as lFEF of sFEF cases according to large or small saccades that were characteristic of the injection site. Projections from the FEF terminated in five frontal regions: 1) area FD on the dorsomedial convexity; 2) area FC (containing SEF) medial to the upper limb of the arcuate sulcus; 3) areas FD and FD delta along the walls of the principal sulcus; 4) area FCBm on the deep, posterior wall of the arcuate sulcus inferior to the sulcal spur; and 5) the inferolateral cortex (area FDi) on the convexity and lateral two thirds of the anterior wall of the arcuate sulcus. Projections in sFEF cases tended to be confined to medial parts of dorsomedial FD and FC and the lateral wall of the principal sulcus and inferolateral convexity. Neither lFEF nor sFEF appeared to project to the SMA or pericingulate cortex. Label in these areas was found only in the cases in which tracer spread into non-FEF areas. FEF projections terminated in column-like patches of about 500-600 microns in diameter. Labeled axons and terminals were seen in all cortical layers regardless of location in the frontal lobe.

Prevention of resistance to IFN-alpha antiproliferative activity: characterization of the effect of IFN-gamma and substitution for IFN-gamma by tumor necrosis factor.

Non-genetic resistance to the antiproliferative effects of interferon-alpha (IFN-alpha) develops in murine and human melanoma cells within 2-4 days of exposure of the cells to IFN-alpha. Simultaneous treatment of murine B16 melanoma cells with MuIFN-gamma and MuIFN-alpha prevents the development of resistance. In this study, the ability of MuIFN-gamma pretreatment to prevent the development of resistance was assessed for varying concentrations of MuIFN-gamma and for varying lengths of time of pretreatment. Pretreatment of the cells for 48 h with MuIFN-gamma using concentrations as low as 5 U/ml prevents the subsequent development of resistance when the cells are cloned in the presence of MuIFN-alpha. Higher concentrations of MuIFN-gamma are more effective in preventing the development of resistance. In addition, short MuIFN-gamma pretreatment times, such as 2-4 h, appeared to be most effective in preventing the development of resistance. In order to determine the mechanism for this biological effect, various second messenger perturbing chemical agents and several other biological agents were screened for ability to prevent the development of resistance. Neither interleukin-2 (IL-2), epidermal growth factor (EGF), nor any of the chemical agents examined could prevent the development of resistance, nor did they alter the ability of MuIFN-gamma to prevent the development of resistance. Tumor necrosis factor (TNF), however, was able to substitute for MuIFN-gamma in preventing the development of resistance, using concentrations of 125 ng/ml and higher.(ABSTRACT TRUNCATED AT 250 WORDS)

The interferons. Mechanisms of action and clinical applications.

The interferons (IFN) are one of the body's natural defensive responses to such foreign components as microbes, tumors, and antigens. The IFN response begins with the production of the IFN proteins (alpha, beta, and gamma), which then induce the antiviral, antimicrobial, antitumor, and immunomodulatory actions of IFN. Recent advances have led to Food and Drug Administration approval of five clinical indications for IFN. Interferon alfa is approved for hairy-cell leukemia, condyloma acuminatum, Kaposi's sarcoma in the acquired immunodeficiency syndrome, and non-A, non-B (type C) viral hepatitis. Interferon gamma has properties distinctive from those of IFNs alpha and beta and is approved as an immunomodulatory treatment for chronic granulomatous disease. Promising clinical results with IFNs have also been reported for basal cell carcinoma, chronic myelogenous leukemia, cutaneous squamous cell carcinoma, early human immunodeficiency virus infection, hepatitis B, and laryngeal papillomatosis. Future clinical uses of IFNs may emphasize combination therapy with other cytokines, chemotherapy, radiation, surgery, hyperthermia, or hormones.