Matrix Metalloproteinase-2 and Tissue Inhibitor of Metalloproteinase-1 in the Retinal Pigment Epithelium and Interphotoreceptor Matrix: Vectorial Secretion and Regulation

Matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) play an essential role in both normal and pathological extracellular matrix degradation, and a TIMP has been associated with at least one type of retinal degeneration. We have studied expression of MMP-2 and TIMP-1 by zymography, immunocytochemistry, and immunoblotting in the retinal pigment epithelium (RPE) from normal, aged and diseased retinas. MMPs and TIMPs were found in the rat RPE, interphotoreceptor matrix (IPM), and in media conditioned by human and rat RPE in culture. In other polarized cells, MMPs and TIMP-2 are secreted vectorially towards the basal lamina. In the RPE, however, MMP-2 and TIMP-1 were secreted preferentially from the apical surface, the surface bordering the IPM. These findings provide new evidence that MMPs and TIMPs could play a role in the turnover of IPM components.Cell homogenates and conditioned media from RPE isolated from mutant Royal College of Surgeons (RCS) rats with inherited retinal dystrophy had similar amounts of MMP-2 and TIMP-1 as those from congenic control rats. The secretion of MMP-2 and TIMP-1 from RPE cell cultures isolated from young and aged human donors varied widely. However, with increasing cell passage number, secretion of MMPs and TIMPs from human RPE increased dramatically. Also, growing human RPE on bovine corneal endothelial cell-generated extracellular matrix instead of plastic reduced the secretion of both MMPs and TIMPs. These data suggest that the integrity of Bruch's membrane may serve to regulate RPE functions in MMP and TIMP secretion and that extracellular matrices contain signals that regulate MMP and TIMP synthesis and/or secretion by the RPE.     

Increased Immune and Inflammatory Responses to Dust Mite Antigen in Rats Exposed to 5 ppm NO2

Immune hypersensitivity to house dust mite antigen (HDM) isa frequent cause of respiratory allergy. The objective of thisstudy was to determine whether exposure to NO₂, a common indoorair pollutant, modulates immune responses to HDM and influencesimmune-mediated lung disease. Brown Norway rats were immunizedip with 100 µg semipurified antigen and Bordetella pertussisadjuvant and challenged 2 weeks later with an intratrachealinjection of 50 µg of a crude antigen preparation. Exposureto 5 ppm NO₂ for 3 hr after both immunization and challengeprocedures resulted in significantly higher levels of antigen-specificserum IgE, local IgA, IgG, and IgE antibody than air controls,and increased numbers of inflammatory cells in the lungs. Lymphocyteresponsiveness to antigen in the spleen and MLN was also significantlyhigher in NO₂-exposed animals. These data show that exposureto a common air pollutant can upregulate specific immune responsesand subsequent immune-mediated pulmonary inflammation.     

Developmental Toxicity of L-Selenomethionine in Macaca fascicularis

Forty pregnant long-tailed macaques were dosed via nasogastricintubation with 0, 25, 150, or 300 µg/kg of L-selenomethionine(Se) daily during organogenesis [Gestational Day (GD) 20–50].Clinical examination of the dams, maternal body weights, sonographicevaluations, clinical chemistry screens, and measures of serumprogesterone and urinary estrone conjugates were used as indicatorsof maternal and fetal status in all animals. The pregnanciesof two to three dams from each dose group were followed untilterm ({small tilde}GD 165); the remainder (N = 7/dose group)were scheduled for hysterotomy on GD 100 ± 2. A standardteratologic evaluation was performed including visceral andskeletal examinations. Fetal liver, kidney, skin, and smooth,cardiac, and skeletal muscles were examined by light microscopy;heart muscle was also evaluated by transmission electron microscopy.Neonates delivered at term remained with the dams and were removedperiodically for morphometric, neurologic, behavorial, and ophthalmologicassessments on Days 1, 8, 15, 22, and 30 of age. Dose-dependentmaternal toxicity as evidenced by anorexia, vomiting, and asignificant reduction in body weight increased with increasingduration of Se exposure. One growth-retarded fetus was recoveredon GD 131 from a compromised dam exposed to 25 /ig/kg-day; oneearly embryonic death (GD 35) and two fetal deaths [GD 68 (followedby maternal death) and GD 123] occurred among animals dosedwith 300 µg/kg-day. Pregnancy loss among treated animalswas not significantly different from concurrent or historicalcontrols. No statistically significant treatment-related effectswere observed at necropsy on GD 100 ± 2. One infant exposedto 150 Mg/kg-day prenatally exhibited a unilateral corticalcataract, which may have been a spontaneous occurrence. Thelimited developmental effects observed and reported teratogenesisin nonmammalian species suggest that comparative pharmacokineticstudies are required before the full public health significanceof elevated Se is understood.     

Separation of the Toxic and Glutathione-Enhancing Effects of the Naturally Occuring Nitrile, Cyanohydroxybutene

Cyanohydroxybutene (CHB) is reported to be hepatotoxic in maleFischer 344 rats at an oral dose of 300 mg/kg and, while nolonger hepatotoxic, pancreatotoxic at 200 mg/kg. In addition,the 200 mg/kg dose causes a persistent elevation in hepaticand pancreatic glutathione (GSH). This study was conducted tode termine if smaller doses of CHB could cause GSH elevationin the absence of toxicity. A single oral dose of 100 mg/kgor multiple lower doses (50 mg/kg daily for 3 days or 30 mg/kgfor 6 days) caused a significant and persistent increase inpancreatic GSH, although hepatic levels were unchanged. Tenmilligrams per kilogram, even daily for 24 days, was withouteffect on hepatic or pancreatic GSH. Neither a single oral doseof 100 mg/kg nor multiple lower doses were associated with toxicity.However, when either 100 or 50 mg/kg were administered intravenously,pancreatic apoptosis was observed. In animals dosed with 100mg/kg iv, mixed histiocytic and suppurative inflammation andfrank pancreatic necrosis also developed and were associatedwith elevated plasma lipase and amylase. The animals receivingCHB intravenously also exhibited elevated GSH levels in bothpancreas and liver. This study shows that oral doses between30 and 100 mg CHB/kg can be used to elevate GSH levels withoutany pancreatotoxicity. However, a single 50 mg CHB/kg dose givenintravenously causes apoptosis, while 100 mg/kg causes severepancreatotoxicity with necrosis.     

What Can Health Communication Science Offer for ACA Implementation? Five Evidence-Informed Strategies for Expanding Medicaid Enrollment

Context: Implementing the Affordable Care Act (ACA) in 2014 will require effective enrollment and outreach efforts to previously uninsured individuals now eligible for coverage.Methods: From 1996 to 2013, the Health Communication Research Laboratory conducted more than 40 original studies with more than 30,000 participants to learn how to improve the reach to and effectiveness of health information for low-income and racial/ethnic minority populations. We synthesized the findings from this body of research and used them to inform current challenges in implementing the ACA.Findings: We found empirical support for 5 recommendations regarding partnerships, outreach, messages and messengers, life priorities of low-income individuals and families, and the information environment. We translated these into 12 action steps.Conclusions: Health communication science can inform the development and execution of strategies to increase the public''s understanding of the ACA and to support the enrollment of eligible individuals into Medicaid or the Health Insurance Marketplace.     

The case control study

The objective of this paper is to review psychiatric problems in children and adults with autism and related disorders and their first-degree relatives, with a focus on: (1) why they present with psychiatric problems; (2) rates of psychiatric disorders; (3) clinical features important in diagnosis and differential diagnosis; (4) treatment. The data come from published reports of psychiatric problems in individuals with autism, Asperger's disorder, or Pervasive Developmental Disorder Not Otherwise Specified and their relatives and the clinical experience of the author and other experts. Children and adults with autism may present with psychiatric problems because of the core defining features of autism, cognitive impairments, medical disorders, other psychiatric symptoms and disorders, and life experiences related to having autism. The data suggest that depression, anxiety, impairing compulsive behaviours, attentional problems, hyperactivity, and sleep problems occur commonly in individuals with autism. Tics and Tourette's disorder appears to occur in a substantial minority. Schizophrenia occurs infrequently. Clinical features of autism and the inapplicability of subjective diagnostic criteria make the diagnosis of other psychiatric disorders difficult in many autistic individuals. Rates of major depression and social phobia are increased in first-degree relatives of autistic probands. The burden of raising an autistic child may also contribute to the development of psychiatric problems in parents and siblings. Future studies need to determine if the risk of developing particular psychiatric disorders and problems is truly increased in individuals with autism and related disorders above the risk in the general population and in individuals with other developmental disorders. If risk is increased, potential risk factors of a genetic, neurologic, cognitive, and environmental nature will need to be identified and understood. In order to measure risk and identify risk factors, reliable, valid methods for diagnosing psychiatric disorders and problems in autistic children and adults must be developed.