A chronic inhalation toxicity/oncogenicity study of methylethylketoxime in rats and mice.

To evaluate the oncogenic potential of methylethylketoxime (MEKO), CD-1 mice (50/sex/group) and F-344 rats (50/sex/group) were coexposed 6 h/day, 5 days/wk for 18 mo (mice) or 26 mo (rats) via whole-body inhalation exposures to target vapor concentrations of 0, 15, 75, and 375 ppm (actual concentrations of 0, 15 +/- 1, 75 +/- 2, or 374 +/- 10 ppm). Satellite groups of rats and mice (10/sex/group/interval) were exposed for 12 mo (mice) and 3, 12, or 18 mo (rats) to evaluate chronic toxicity. Methyl ethyl ketone (MEK), a possible hydrolysis product of MEKO, was present at less than 1%. Treatment-related effects included increased body weight (male rats only), methemoglobin formation, hematology and clinical chemistry changes, increased liver weight, and increased spleen and testes weights (rats only). A high incidence of cataracts and corneal dystrophy occurred in both control and MEKO-exposed rats, with an earlier appearance and slightly higher incidence for these ocular lesions in MEKO-exposed animals compared to controls. Degenerative and reparative changes of the olfactory epithelium in the nasal turbinates, primarily limited to the dorsal meatus, occurred in both rats (75 and 374 ppm) and mice (15, 75, and 374 ppm). In addition, in the mice, liver changes included increased incidences of pigment in reticuloendothelial cells, centilobular hypertrophy, granulomatous inflammation, and a slightly increased incidence of necrosis (75 and 374 ppm). An increase in hepatocellular carcinomas occurred in male mice at 374 ppm. Additional MEKO-related findings in the rat included congestion of the spleen with pigment in reticuloendothelial cells and extramedullary hematopoiesis and a decreased incidence of lymphoreticular mononuclear cell leukemia. Effects observed in the liver of the rats included decreases in the incidence of both peribiliary fibrosis and hyperplasia/proliferation of the biliary duct, an increase of spongiosis hepatis in males, and an increase in the incidence of intracytoplasmic vacuoles and hepatocellular basophilic foci. The effects on the liver were generally most profound in the high-exposure groups and, with the exception of the spongiosis hepatis, occurred in both sexes. An increase in hepatocellular adenomas occurred in the male rats at 75 and 374 ppm, and hepatocellular carcinomas in the male rats at 374 ppm. In both species, the liver tumors appeared relatively late in the life of the animals, with no significant increase in tumors at 12 mo of exposure in mice and at 18 mo of exposure in rats. Lifespan shortening was not observed, as MEKO-exposed animals survived generally as well as, or slightly better than, the controls.

Pax-6 expression and activity are induced in the reepithelializing cornea and control activity of the transcriptional promoter for matrix metalloproteinase gelatinase B.

Recent evidence supports the idea that matrix metalloproteinases (MMPs) act as morphogenetic regulators in embryonic and adult events of tissue remodeling. MMP activity is controlled primarily at the level of gene expression. In a recent study we characterized the transcriptional promoter of the MMP gene, gelatinase B (gelB), in transgenic mice, demonstrating the requirement for DNA sequences between -522 and +19 for appropriate activity. In this study we investigated factors required for gelB promoter activity in the developing eye and reepithelializing adult cornea. Pax-6 is a homeobox and paired domain transcription factor that acts at the top of the hierarchy of genes controlling eye development. Pax-6 is also expressed in the adult eye. We show here that the tissue expression pattern of Pax-6 overlaps extensively with gelB promoter activity in the developing and adult eye. In addition Pax-6 is observed to be upregulated in repairing corneal epithelium, as is gelB promoter activity. In cell culture transfection experiments, we identified two promoter regions which mediate positive response to Pax-6. By electrophoretic mobility shift assay, we further pinpoint two Pax-6 binding sites within these response regions and demonstrate direct interaction of the Pax-6 paired domain with one of these sites. These data suggest a mechanism by which Pax-6 may direct gelB expression in an eye-specific manner.

Thirteen-week subchronic rat inhalation toxicity study with a recovery phase of trivalent chromium compounds, chromic oxide, and basic chromium sulfate.

The toxicity of trivalent chromium compounds; chromic oxide and basic chromium sulfate, was investigated in rats in a 13-week nose-only inhalation study that included a 13-week recovery period. Nose-only exposures to insoluble chromic oxide dust at 4.4, 15, or 44 mg/m3 or soluble basic chromium sulfate dust at 17, 54, or 168 mg/m3 (trivalent chromium equivalent concentrations of 3, 10, and 30 mg/m3) were carried out for 6 h/day, 5 days/week. No compound-related mortality occurred. General toxic effects, only observed with high-exposure levels of basic chromium sulfate, included sporadic signs of labored breathing and depressed body weights. No apparent compound-related effects were noted for sperm motility or morphology, for any concentration of either test material. Bronchoalveolar lavage fluid evaluations showed test material in mononuclear cells with chromic oxide and increased neutrophils, protein, lactic dehydrogenase and cellular debris with basic chromium sulfate. The principle effects for both materials were primarily to the respiratory tract. Chromic oxide caused pathological changes in the bronchial and mediastinal lymphatic tissue and lungs, consisting of the presence of pigment-laden macrophages, lymphoid and septal hyperplasia, and interstitial inflammation similar to that observed with other inert dusts. Basic chromium sulfate produced more severe and widespread effects in the nasal cavity, larynx, lungs, and mediastinal lymph node. Effects were characterized by accumulation of foreign material, infiltration of alveolar macrophages, septal cell hyperplasia, and granulomatous and chronic inflammation. Pigment was still present in chromic oxide and, to a lesser extent, in basic chromium sulfate-treated animals after the 13-week recovery period, with partial recovery of the pathological lesions. A NOAEL was not established for either test material, but 4.4 mg/m3 was thought to be near the NOAEL level for subchronic exposure to chromic oxide. The results of this study indicate significant differences in toxicity to the respiratory tract between trivalent chromium compounds chromic oxide and basic chromium sulfate. These are likely related to differences in acidity and water solubility, rather than chromium concentration per se. This conclusion is substantiated by the lack of effect on other internal organs.

Subchronic inhalation toxicity study of caprolactam (with a 4-week recovery) in the rat via whole-body exposures.

This study was designed to assess the potential subchronic inhalation toxicity of caprolactam when administered as a 3-micron aerosol from an aqueous solution to Sprague-Dawley CD rats (10/sex/group) via whole-body exposure. The study was enhanced with the inclusion of motor activity measurements and a functional observational battery to assess the neurotoxic potential of caprolactam. The rats were exposed at least 65 times over a 13-week period for 6 h per day, 5 days per week, to target concentrations (3 microns, mass median aerodynamic diameter) of 0, 25, 75, and 250 milligrams per cubic meter (mg/m3). An additional 10 animals/sex/group were similarly exposed and then held for a 4-week recovery period. Exposure levels were determined gravimetrically six times daily; one daily sample was analyzed by high-pressure liquid chromatography. No deaths were observed in the study during the exposure or recovery periods. Treatment-related responses such as labored breathing and nasal discharge were seen during many of the exposures. Similar responses as well as moist rales were seen during the nonexposure periods during the 13 weeks of exposure. However, these responses abated during the 4-week recovery period. There were no clearly treatment-related responses observed with ophthalmoscopic examinations, body weight measurements, food consumption measurements, neurobehavioral evaluations, clinical pathology evaluations, organ weight measurements, or macroscopic pathology examinations. Microscopic findings that were considered related to exposure to the test material were seen in the nasoturbinal tissues (hypertrophy/hyperplasia of goblet cells in the respiratory mucosa and intracytoplasmic eosinophilic material in epithelial cells of the olfactory mucosa) of the two higher-exposure group animals and in the laryngeal tissues (squamous/squamoid metaplasia/hyperplasia of the pseudostratified columnar epithelium covering the ventral seromucous gland) of all three exposure group animals. These changes were considered to be adaptive responses to an irritant (caprolactam). The keratinization of the metaplastic epithelium in the larynx was considered to be an adverse effect. By the end of the 4-week recovery period, there was complete regression of the keratinization in the larynx, but recovery of the adaptive nasoturbinal effects had not completely resolved. In conclusion, the whole-body exposure of Sprague-Dawley rats to caprolactam as a respirable aerosol for 6 h/day, 5 days/week, for 13 weeks at gravimetrically determined levels of 24, 70, and 243 mg/m3 resulted in respiratory tract effects (laryngeal) at the highest exposure level with complete recovery within 4 weeks postexposure. The results indicate that the no-observed-adverse-effect level for caprolactam is 70 mg/m3, based on upper respiratory effects, with 243 mg/m3 representing a no-observed-effect level for systemic toxicity, neurotoxicity, and lower respiratory tract effects.

Gelatinase B/lacZ transgenic mice, a model for mapping gelatinase B expression during developmental and injury-related tissue remodeling.

Matrix metalloproteinases (MMPs) drive normal tissue remodeling and are implicated in a wide range of pathologies. Although MMP activity is controlled at multiple levels, the primary regulation of MMP activity is transcriptional. The transcriptional promoter elements required for MMP gene expression in cultured cells have been defined, but this has not been extended to the in vivo situation. In this paper, we show that the DNA sequences between -522 and +19 of the rabbit gelatinase B gene (MMP-9) (as characterized in the transgenic mouse line 3445) constitute a minimal promoter that drives appropriate developmental and injury-induced reporter gene expression in transgenic mice. We further show that the expression and activity of three transcription factors (NF-kappaB, AP-2, and Sp1) that control the activity of the gelatinase B promoter are selectively induced in the epithelium migrating to heal a wound. Although promoter activity parallels expression of the endogenous gene in cell cultures, we show by several criteria that cell cultures cannot model many aspects of promoter regulation in vivo. This study reveals that the transgenic mouse line 3445 might be a useful model for investigating the regulation of gelatinase B expression in vivo and for identifying and characterizing new drugs that can control gelatinase B gene transcription.

GATHER guide to counseling.

PIP: Counseling about family planning (FP) and other reproductive health issues requires a set of specific skills designed to facilitate informed decision-making. The GATHER approach to counseling--Greet, Ask, Tell, Help, Explain, and Return--has documented effectiveness in FP programs. The more of the GATHER elements a counselor uses, the more satisfied clients are with their care and the more likely they are to use contraception. This guide provides detailed information on each of the 6 elements of the GATHER model, including key phrases, sample provider actions, and teaching exercises. A chart presents information on available FP methods--mechanism of action, advantages, disadvantages, use requirements, and follow-up. Special sections address topics such as FP for women who are breast feeding, emergency oral contraception, and counseling adolescents. Other sections offer guidelines on responding to a client's feelings, "active listening," talking about sex comfortably, and advising without being controlling. Finally, a checklist is included so counselors can rate themselves on each of the GATHER skills. An earlier version of this guide has been used around the world for the past 10 years.^ieng

Regulation of paracrine cytokine balance controlling collagenase synthesis by corneal cells.

PURPOSE: Classic studies have demonstrated that corneal epithelial cell density in culture can alter the balance of stimulatory and inhibitory cytokines controlling the elaboration of collagenolytic activity by co-cultured stromal cells. The current study attempts to bring the understanding of this mechanism to a molecular level. METHODS: A rabbit primary corneal cell culture model was used. RESULTS: Using molecular probes that bind to and neutralize specific cytokines, a major stimulator for stromal cell collagenase synthesis released by corneal epithelial cells into culture medium was identified as interleukin-1 alpha (IL-1 alpha), and a secondary stimulator was characterized as a heparin-binding cytokine. An inverse relationship between net collagenase stimulatory activity and epithelial cell plating density was demonstrated. In contrast, the release of inhibitory activity for IL-1-stimulated collagenase synthesis was not subject to the cell density effect. Direct measurement of IL-1 alpha protein levels revealed that this cytokine was released much more efficiently on a per cell basis when cells were plated at low density than when they were plated at high density. The effect was not caused by greater cell lysis at low cell density and was mediated only partially by changes at the IL-1 alpha synthesis level. CONCLUSIONS: These data provide evidence that epithelial cells release stimulatory cytokines for collagenase expression more efficiently when they have limited contact with their neighbors and that this has important consequences for the overall paracrine cytokine balance controlling collagenase synthesis. Alteration of the paracrine cytokine balance by changes in cell contact may be an important means for regulating epithelial-stromal interactions involved in corneal development and repair.

Role of serum amyloid A as an intermediate in the IL-1 and PMA-stimulated signaling pathways regulating expression of rabbit fibroblast collagenase.

The matrix metalloproteinase collagenase is expressed by resident tissue cells only when needed for biological remodeling. Exogenous addition of inflammatory and growth-promoting cytokines stimulates collagenase expression in early passage fibroblast cultures. In addition, the signal for collagenase expression in response to phorbol-12 myristate-13 acetate (PMA) or to agents which alter cell shape in early passage fibroblast cultures is routed extracellularly to an autocrine cytokine intermediate, IL-1 alpha. Importantly, fibroblasts, when freshly isolated from the tissue, are not competent for IL-1 alpha gene expression and, therefore, cannot produce collagenase in response to shape change agents. However, they do make a small amount of collagenase in response to PMA via an IL-1-independent pathway that has not been further characterized. In this paper, we investigate the role of a second autocrine, serum amyloid A3 (SAA3), in IL-1-dependent and -independent collagenase gene expression. We demonstrate that SAA3 is required for effective stimulation of collagenase expression by either exogenous or endogenous IL-1. Furthermore, while freshly isolated fibroblasts cannot express IL-1 alpha they can express SAA3, and this autocrine mediator acts independently of IL-1 alpha to control the low level of collagenase expression that can be stimulated by PMA. These results provide further evidence for a newly emerging paradigm of collagenase regulation which emphasizes the requirement for extracellular routing of signals. They also suggest that SAA3 might be utilized independently of IL-1 alpha to control tissue remodeling in vivo.

Role of matrix metalloproteinases in failure to re-epithelialize after corneal injury.

Delayed re-epithelialization of the cornea after injury usually precedes stromal ulceration. Previous findings using a rat thermal injury model suggested that re-epithelialization is impeded by products of resident corneal cells, which destroy adhesive structures at the basement membrane zone. In this study, we provide additional evidence for this concept. Failure to re-epithelialize was found to correlate with an increase in the amounts of gelatinolytic matrix metalloproteinases present in the rat cornea. One of these gelatinases, gelatinase B, is synthesized by the resident corneal cells, and inhibitions of its synthesis correlated with inhibition of basement membrane dissolution. The matrix metalloproteinases collagenase and stromelysin are also synthesized by resident corneal cells in thermally injured corneas of rabbits, but the timing of bulk enzyme synthesis correlated more closely with deposition of repair tissue in the stroma than with failure to re-epithelialize. Nevertheless, in human corneas with repair defects, gelatinase B and collagenase are synthesized by cells in the basal layer of the epithelium directly adjacent to the basement membrane, suggesting that both could participate in dissolution of this structure. Importantly, treatment of thermally injured corneas with a synthetic inhibitor of matrix metalloproteinases significantly improved basement membrane integrity. These data support the concept that over-expression of matrix metalloproteinases by resident corneal cells impedes re-epithelialization after some types of corneal injury.

Reproductive toxicity evaluation of methylethyl ketoxime by gavage in CD rats.

Methylethyl ketoxime (CAS No. 96-29-7; MEKO; 2-butanone oxime), an antioxidant agent used in paints, resins, and adhesives, was tested for reproductive toxicity in a two-generation study with CD (Sprague-Dawley) rats. Thirty-eight-week-old rats/sex/group (F0) were administered MEKO in water, by gavage, at 0, 10, 100, or 200 mg/kg/day (at a dosing volume of 2 ml/kg), 5 days/week for 10 weeks with vaginal cytology evaluation (VCE) of F0 females during the last 3 weeks of the prebreed period. Animals were mated within groups for 3 weeks with dosing during mating, gestation, and lactation for 7 days/week. F0 parents and F1 weanlings, 10/sex/dose, were necropsied (after a 2-week postwean VCE in F0 females) with hematologic evaluation (including methemoglobin) and histology of adult livers, spleens, and reproductive organs. F1 weanlings, 30/sex/dose, were dosed for 11 weeks and mated as described above. Because of poor reproductive performance, not treatment related, F1 animals with no F2a litters were rebred to produce F2b litters. F1 parents and F2a weanlings, 10/sex/dose, were necropsied and evaluated as described above. Inguinal mammary glands were examined histologically from all nonselected F1 and F2 (a and b) female weanlings. Adult toxicity was observed in both generations and both sexes at all doses. Treatment-related parental deaths occurred at 200 mg/kg/day. At 100 and 200 mg/kg/day, parents exhibited dose-related reduced body weights and weight gains, reduced feed consumption, clinical signs of toxicity, and anemia with concomitant extramedullary hematopoiesis and hemosiderosis in livers and spleens (and increased spleen weights). At 10 mg/kg/day, only adult liver and spleen histologic effects were present. There was no evidence of reproductive organ or mammary glad pathology or of reproductive or postnatal toxicity at any dose tested. There was no adult "no observable adverse effect level" (NOAEL) established; the NOAEL for reproductive and postnatal toxicity was at least 200 mg/kg/day for rats in this study.

A corneal epithelial inhibitor of stromal cell collagenase synthesis identified as TGF-beta 2.

PURPOSE: To determine the molecular mechanisms whereby substances released by corneal epithelial cells act to inhibit the elaboration of collagenolytic activity by corneal stromal cells and to determine whether inhibitory activity might be mediated by interleukin-1 receptor antagonist (IL-1ra) or transforming growth factor (TGF)-beta. METHODS: Conditioned media were generated from primary cultures of rabbit corneal epithelial cells, from passaged cultures of rabbit corneal stromal fibroblasts, and from cells of the rabbit corneal epithelial cell line, SIRC. Pure populations of stromal cells were isolated from rabbit cornea and used directly for bioassay of the conditioned media to detect substances that inhibit collagenase synthesis. The mink lung epithelial cell line, Mv1Lu, was used for bioassay of TGF-beta-like activity. The addition of specific neutralizing antisera to bioassays allowed an assessment of the contribution of each isoform to the net regulatory activity. Reverse transcription-polymerase chain reaction and Northern blot analysis were employed to detect the presence of IL-1ra or TGF-beta mRNA species in cells from cultures used to generate conditioned media. RESULTS: Both stimulatory and inhibitory substances that regulate the synthesis of stromal cell collagenase are released by corneal epithelial cells in primary culture. In contrast, only stimulatory activity is produced by corneal fibroblasts or SIRCs. MRNAs for a TGF-beta isoform, TGF-beta 2, and IL-1ra were identified in epithelial cells. Stromal fibroblasts also expressed TGF-beta 2 mRNA, but no evidence was found for expression of TGF-beta 3 mRNA in any of the three cell types. TGF-beta 2 is released by epithelial cells in both active and latent forms. This cytokine mediates the major portion of the net inhibitory activity against stromal cell collagenase synthesis produced by corneal epithelial cells. CONCLUSIONS: This study demonstrates the expression of TGF-beta 2 and IL-1ra by corneal epithelial cells in culture. It is the TGF-beta 2 that acts as the major inhibitor of collagenase synthesis by corneal stromal cells in culture. However, IL-1ra and TGF-beta 2 are likely to play important roles in epithelial-mesenchymal interactions regulating corneal development, homeostatic maintenance, and repair.

The rabbit gene for 92-kDa matrix metalloproteinase. Role of AP1 and AP2 in cell type-specific transcription.

We isolated the rabbit gene for the 92-kDa matrix metalloproteinase, gelatinase B, and sequenced 1802 contiguous bases covering the first three exons and 522 bases of DNA upstream of the start site for transcription. The DNA between bases -519 and +19 is sufficient to drive expression of a reporter gene in early passage cultures of corneal fibroblasts or primary cultures of corneal epithelial cells. Basal activity of the gelatinase B promoter in fibroblasts is lower than a collagenase promotor of 1800 base pairs, but activity of both promotors is similarly stimulated by treatment of transfected cells with phorbol 12-myristate 13-acetate, and stimulation is enhanced by co-treatment with transforming growth factor-beta. In contrast, basal activity of the gelatinase B promotor in epithelial cells is higher than the collagenase promotor. Deletion analysis demonstrated that sequences upstream of base -330 confer cell type-specific activity to the gelatinase B promotor. Site-directed mutagenesis revealed that an AP1-like element within this region is specifically utilized by fibroblasts. This region also contains elements that confer the capacity for activation by AP2, a transcription factor found to be expressed by corneal epithelial cells but not by corneal fibroblasts. In contrast, AP2 does not activate the collagenase promotor. These results provide a molecular basis for the unique cell type-specific expression pattern of gelatinase B as compared to other matrix metalloproteinases.

Interleukin 1 alpha mediates collagenase synthesis stimulated by phorbol 12-myristate 13-acetate.

Stimulation of collagenase expression in cultures of normal diploid fibroblasts by the tumor promotor phorbol 12-myristate 13-acetate (PMA) occurs secondarily to synthesis of unknown intermediary proteins. We have investigated the hypothesis that a form of the cytokine interleukin 1 (IL-1) is one intermediate controlling PMA-stimulated collagenase expression. Treatment with an IL-1 receptor antagonist inhibits the constitutive synthesis of collagenase in early passage fibroblast cultures from rabbit. Radioimmunoassay demonstrates that, of the two known IL-1 forms, IL-1 alpha and IL-1 beta, only IL-1 alpha is synthesized and released into the medium of corneal fibroblast cultures. PMA treatment of cells increases the level of IL-1 alpha mRNA; this occurs prior to the increase in collagenase mRNA and corresponds with increased synthesis and release of IL-1 alpha protein. Neutralizing antiserum to IL-1 alpha inhibits constitutive collagenase synthesis. Reagents that inhibit the activity of IL-1 alpha (IL-1 receptor antagonist or neutralizing antibody) also inhibit the PMA-mediated stimulation of collagenase synthesis. These results indicate that constitutive and PMA-stimulated expression of collagenase is regulated through an IL-1 alpha intermediate. In vivo, regulation of the lytic phase of tissue remodeling through the IL-1 alpha intermediate may ensure the recruitment of cells adjacent to the one that received the initial stimulus.

Toxicity of calcium sodium metaphosphate fiber. II. Chronic inhalation and oncogenicity study.

Male and female Fischer 344 rats (80/sex/group) were exposed to CSM fiber 6 hr/day, 5 days/week at target-exposure levels of 0, 1, 5, or 25 mg/m3 for 24 months, corresponding to 0, 27, 80, and 513 fibers/cc, respectively. Number and size of the airborne fibers were determined during the course of the study. At 3 and 12 months, 10 rats/sex/group were euthanized and at 18 and 24 months 5 rats/sex/group were euthanized. In addition, 5 rats/sex/group were removed from exposure at 18 months and maintained for a 6-month recovery period. All animals surviving at the completion of the exposure period were maintained in a clean environment for up to 5 additional months. Clinical laboratory examinations were performed on 10 animals/sex/group at 3, 12, and 24 months. The number of fibers in the lung were also determined at 3, 12, 18, and 24 months. Body weight and survival did not appear to be affected by treatment. There were no biologically significant effects on clinical parameters. There was a dose-related increase in lung weight during the exposure period which was generally reversible during the recovery periods. There also was a dose-related increase in the number of fibers/milligram of lung, but no increase in lung fiber burden after the first 3 months. The number of fibers in the lungs of animals exposed to CSM fiber for 18 months and allowed 6-month recovery period showed a decrease especially at the high dose. No increase in tumors (benign or malignant) was observed in this study. Microscopic changes considered reflective of an irritant response were observed in the nasal turbinates notably at the 5 and 25 mg/m3 levels. Histological changes were also observed in the lungs at the 5 and 25 mg/m3 levels. The incidence and/or severity of histopathological changes in the 1 mg/m3 group was considered to be essentially comparable to controls.

Characteristics of a glycoprotein in the ocular surface glycocalyx.

A monoclonal antibody has been produced that binds to the apical squames (flattened cells) of the rat ocular surface epithelium and to the goblet cells of the conjunctiva. Immunoelectron microscopic localization of the antigen indicates that in apical cells it is present along the apical-microplical membrane in the region of the glycocalyx. In subapical squames, the antigen is in cytoplasmic vesicles. In some goblet cells, the antigen is in the Golgi network, and in others, it is located primarily in the membrane of the mucous granules. SDS-PAGE and immunoblot analysis demonstrate that the molecular weight of the antigen is greater than 205 kD, and the electrophoretic band stains with Alcian blue followed by silver stain. Periodate oxidation of immunoblots and cryostat sections removes antibody binding. Neuraminidase treatment of cryostat sections does not remove antibody binding, whereas N-glycanase does. Taken together, these data indicate that the antigen recognized by the monoclonal antibody is a carbohydrate epitope on a high-molecular-weight, highly glycosylated glycoprotein in the glycocalyx of the ocular surface epithelium and goblet cell mucin granule membrane. The antigen appears to be stored within cytoplasmic vesicles and reaches the glycocalyx when cells differentiate to the apical-most position where the glycocalyx interfaces with the mucin layer of the tear film.

Time to talk condoms.

PIP: A great deal of avoided if political and religious leaders, educators, health care providers and the mass media would band together in an effort to promote condom use. Condoms use protects against unwanted pregnancies, STDs and AIDS. Yet, public discussions on condom use are rate. In the US, political leaders avoid mentioning the topic, and television networks severely restrict the airing of public service announcements for condoms. Worldwide, an estimated 100 billion acts of sexual intercourse take place every year. A recent report indicates that it would take a modest 13 billion condoms a year to protect everyone who is at risk of contracting AIDS and other STDs, and risk of having an unwanted pregnancy. Currently, worldwide production of condoms stands at about 6 billion a year. Furthermore, condom makers have the capacity to increase production by some 2 billion, and could add new capacity in about 2 years. Many believe that marketing condoms is a difficult enterprise, since men often report that condoms reduce pleasure, cause embarrassment, or are not available when needed. The challenge for markets, then, is to create demand. This is especially true in the US, where prime-time advertising and the use of popular entertainment, such as soap operas, could promote condoms as both safe and satisfying. In the developing world, the challenge is to make condoms widely available and affordable. Some changes have taken place since 1981, when AIDS first came into the spotlight. In the US, people now discuss the topic of STDs more openly. But an all-out effort to promote condom use has not yet begun.^ieng

The health hazards posed by chromium-contaminated soils in residential and industrial areas: conclusions of an expert panel.

Between 1905 and 1971, over 2 million tons of residue from chromite ore processing was generated in Hudson County, New Jersey, of which substantial amounts were used as fill and tank diking. A panel of medical, toxicology, and risk assessment experts was convened in early 1990 to evaluate the potential health hazards posed by the resulting chromium contaminated soil. The Panel concluded that soils containing concentrations of 75 ppm hexavalent chromium [Cr(VI)] and 1000 ppm total chromium compounds (about 95% was trivalent chromium [Cr(III)]) did not pose a significant health hazard to nearby residents and workers. They also determined that exposure to chromium from Hudson County sites posed a negligible cancer hazard to residents. Using risk assessment methods, the Panel estimated that the plausible incremental cancer risk to individuals at residential sites would be substantially less than 1 in 1,000,000. The average measured levels of airborne Cr(VI) at typical industrial sites were more than 1000-fold lower than the current OSHA Permissible Exposure Limit (PEL). The maximum plausible increased cancer risk for an average worker at a dusty industrial site was estimated to be less than 1 in 100,000. The Panel also concluded that chromium-containing crystals, which have occasionally been found in Hudson County buildings, do not pose a significant hazard. However, they suggested that were the concentration to exceed 5000 ppm Cr(VI) in the crystals, site-specific health risk assessments would be conducted and remediation considered. The Panel evaluated the dermal hazard posed by chromium-contaminated soil and acknowledged that there is a small group of persons (approximately 0.1% of the United States population) who currently have a dermal sensitization to Cr(VI) primarily through occupational exposure. Based on published studies of human volunteers, the Panel concluded that a small percentage (less than 5%) of persons already sensitized may respond to Cr(VI) in solution at concentrations above 35 ppm. They decided that a much higher concentration in soil, perhaps 350 ppm Cr(VI), would be necessary to elicit dermatitis because only a fraction of the chromium in soil is soluble. The Panel concluded that it was highly unlikely (if not impossible) for a person to become dermally sensitized to Cr(VI) or Cr(III) at the soil concentrations found in most areas in Hudson County.(ABSTRACT TRUNCATED AT 400 WORDS)

Norrie disease gene is distinct from the monoamine oxidase genes.

The genes for MAO-A and MAO-B appear to be very close to the Norrie disease gene, on the basis of loss and/or disruption of the MAO genes and activities in atypical Norrie disease patients deleted for the DXS7 locus; linkage among the MAO genes, the Norrie disease gene, and the DXS7 locus; and mapping of all these loci to the chromosomal region Xp11. The present study provides evidence that the MAO genes are not disrupted in "classic" Norrie disease patients. Genomic DNA from these "nondeletion" Norrie disease patients did not show rearrangements at the MAOA or DXS7 loci. Normal levels of MAO-A activities, as well as normal amounts and size of the MAO-A mRNA, were observed in cultured skin fibroblasts from these patients, and MAO-B activity in their platelets was normal. Catecholamine metabolites evaluated in plasma and urine were in the control range. Thus, although some atypical Norrie disease patients lack both MAO-A and MAO-B activities, MAO does not appear to be an etiologic factor in classic Norrie disease.

Monoamine oxidase deficiency in males with an X chromosome deletion.

Mapping of the human MAOA gene to chromosomal region Xp21-p11 prompted our study of two affected males in a family previously reported to have Norrie disease resulting from a submicroscopic deletion in this chromosomal region. In this investigation we demonstrate in these cousins deletion of the MAOA gene, undetectable levels of MAO-A and MAO-B activities in their fibroblasts and platelets, respectively, loss of mRNA for MAO-A in fibroblasts, and substantial alterations in urinary catecholamine metabolites. The present study documents that a marked deficiency of MAO activity is compatible with life and that genes for MAO-A and MAO-B are near each other in this Xp chromosomal region. Some of the clinical features of these MAO deletion patients may help to identify X-linked MAO deficiency diseases in humans.