Breast Implant info part 2

[Guest guest]

From the website:http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=117237

BackgroundThe effect of silicones on the immune function is not fully characterized.In clinical and experimental studies, immune alterations associated withsilicone gel seem to be related to macrophage activation. In this work weexamined in vivo, phenotypic and functional changes on peritonealmacrophages early (24 h or 48 h) and late (45 days) after theintraperitoneal (i.p.) injection of dimethylpolysiloxane (DMPS) (silicone).We studied the expression of adhesion and co-stimulatory molecules and boththe spontaneous and the stimulated production of reactive oxygenintermediates and nitric oxide (NO). ResultsThe results presented here demonstrate that the fluid compound DMPS induceda persistent cell recruitment at the site of the injection. Besides, cellactivation was still evident 45 days after the silicone injection: activatedmacrophages exhibited an increased expression of adhesion (CD54 and CD44)and co-stimulatory molecules (CD86) and an enhanced production of oxidantmetabolites and NO. ConclusionsSilicones induced a persistent recruitment of leukocytes at the site of theinjection and macrophage activation was still evident 45 days after theinjection. BackgroundNowadays we are in permanent contact with silicones, synthetic polymerscontaining a repeating Si-O backbone and organic groups attached to thesilicon atom [1<http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=117237#B1> ].Medical-grade silicones consist primarily of dimethylpolysiloxane (DMPS) andare widely used in devices including cardiac valves, intravenous tubing,intraocular lenses, digital joint arthroplasty prostheses, breast implants,syringes, needles, baby bottle nipples and many others products [1<http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=117237#B1> ].Depending upon the length of the polymer chains and the amount ofcross-linking between chains medical-grade silicones can be found as fluids,gels or elastomers.The effect of silicones on the immune function is not fully characterized.It has been shown that certain forms of silicone are immunologically active[2 <http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=117237#B2> ]and depending upon the molecular weight and the degree of cross-linking ofthe polymers, silicones are potent humoral adjuvants [3<http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=117237#B3> ].Several studies of the silicone-induced inflammatory response in patientsand animals revealed histopathological findings instead of direct evidencesof cellular activation [4<http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=117237#B4> -6<http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=117237#B6> ].The initial body's reaction to the implanted material is the inflammatoryresponse that induces recruitment and activation of different cells [7<http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=117237#B7> ]. Themagnitude of any inflammatory response can be related to the level ofactivation of macrophages. This activation occurs both in inflammatory andin adaptive immune responses, and involves phenotypic and functional changes[8 <http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=117237#B8> ].Criteria widely used for activation are the ability to inhibit intracellularproliferation of microorganisms, the increased production of reactive oxygenintermediates and the enhanced expression of MHC and co-stimulatorymolecules [9<http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=117237#B9> ,10<http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=117237#B10> ].Recently, Naim et al. showed that silicone elastomer preadsorbed with plasmaproteins activated human monocytes in vitro to secrete pro-inflammatorycytokines [11<http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=117237#B11> ].Besides, silicone gels and oils activated macrophages in female A.SW mice:increased production of IL-6 and IL-1â was obtained from macrophagescollected from silicone fluid- and silicone oil-treated mice when culturedwith increasing amounts of lipopolysaccharide

http://www.fda.gov/cdrh/ost/reports/fy98/IMMUNOTOX.HTM

Endocrine Disruption by Medical Device Materials

Key words: estrogen disruption, uterotrophic assay, heat shock proteins, bisphenol A

CDRH is concerned with the potential for certain medical device materials to mimic or interfere with endogenous hormone actions. Because the hormone estrogen is a potent molecule having profound effects at remarkably low doses, assays are needed to assess the potential for harm from materials that may induce unwanted effects due to interference with normal estrogen homeostasis. OST scientists are collaborating with researchers at the Department of Biology, Washington University, on projects focused on improving the use of a key biomarker of exposure to estrogenic compounds and determining the characteristics of the estrogenic activity of bisphenol A, a plasticizer found in some medical devices.

OST scientists are modifying and enhancing the traditional assay for estrogenic effects. The traditional assay utilizes the ability of estrogen to cause a hypertrophy of the uterus in ovariectomized or immature female mice. The purpose of these modifications is to provide mechanistic information that will reduce the number of uncertainties in assessing risk from exposure to estrogenic materials. OST scientists are developing an assay that promises to do just that: obtain mechanistic information while examining estrogenic responses in the whole animal. This is accomplished by a side-by-side comparison of the traditional uterotrophic assay and a specific cellular event, the induction of stress proteins, that occurs when estrogen or estrogen-mimicking materials bind to its specific cellular receptor.

Stress, or heat shock, proteins are synthesized rapidly by most cells in response to various chemical and physical stressors, especially heat. This response is thought to serve a cellular protective function. Other functions have been found, and heat shock proteins are called "chaperones" because they appear to associate with other proteins and hold them in proper conformations. This appears to be their function in relation to steroid hormone receptors: they appear to hold the receptor molecule in an open position, so that the receptor can bind to ligand easily. When the ligand binds, the heat shock protein dissociates; the receptor is free to assume a new shape, one that retains the bound ligand but which also enables the receptor to bind the correct sequence on the genomic DNA, called the hormone responsive element. Thus, OST has tried to identify changes in heat shock proteins as a marker of estrogen receptor binding in tissues from whole animals treated with estrogens.

OST scientists have shown that such changes can be detected in a number of heat shock proteins in the uterus in response to estrogen and that the response is specific to uterine and estrogenic compounds. The effect of exposure time on changes in heat shock proteins was assessed in ovariectomized mice treated with estradiol, the primary estrogen form in the body. Increased relative uterus weight increased linearly between the 4-hour , 8-hour, and 12-hour post-exposure time points, and remained for 1 and 2 days. The histopathology of the uterine lining showed a similar pattern. Changes in the pattern of heat shock protein expression were observed between 6 and 12 hours post-treatment. Thus all three endpoints examined appear at approximately the same time after treatment. This is consistent with the idea that the heat shock protein changes are related specifically to the estradiol effects.

Other steroid and steroid-like compounds were used in order to examine the specificity of the response. The compounds included an androgen, an androgen-receptor antagonist, a progestin, and a partial estrogen. These compounds induced changes in heat shock protein expression, but did not induce uterine swelling. This result demonstrates that the heat shock protein changes are not the result of the stresses to the cells caused by uterine swelling, and the heat shock response may be more sensitive than the uterine response. Compound ICI 182,780, a potent anti-estrogen, had no effect on uterine weights and did not induce changes in heat shock proteins. However, the highest dose of the ICI compound blocked the uterine and heat shock protein effects of co-administered estradiol. Thus heat shock protein induction: 1) is an estrogenic effect independent of uterine swelling; and 2) is a more sensitive indicator of estrogenic effect than is uterine swelling. The histological changes occur in parallel with the uterine swelling effects.

The three endpoints (uterine hypertrophy, histology, and stress protein expression, were used to examine the estrogenic response of the plasticizer bisphenol A. Bisphenol A was determined to be less estrogenic that estradiol (by more than 1000-fold), but caused similar effects. Histological changes in the uterine epithelia were observed at doses 40-fold lower than doses that caused uterine swelling. Although responses were variable, heat shock protein induction was also more sensitive than the uterotrophic response.

Immunological Responses to Silicone Breast Implants

Key words: autoantibodies, silicone breast implants, immunopathology

The breast implant experiments were accomplished in two parts: first to demonstrate immune responses to silicone gel implants in an animal model; and second, to apply the experimental protocols to samples from women with/without breast implants. The objective of these studies was to determine which autoimmune-like symptoms and other symptoms are associated with implanted materials.

OST has developed a rat model to study and understand immune responses to silicone gel and oil used in breast implants. This model included normal rats and a strain of autoimmune rats, that mimicked clinical conditions found in patients with silicone gel breast implants. Mixtures of silicone gel/oil were injected into the mammary area of female rats. Scientists then measured the levels of autoantibodies to collagen and to nuclear proteins developed over 2 years in response to these mixtures.

Results from the rat model indicate that specific autoantibodies may be induced by certain biomaterials. The immune system recognizes a biomaterial-connective tissue protein association as altered-self or as foreign. OST scientists have demonstrated that medical grade silicone oil can stimulate serum autoantibodies against collagen and against DNA when this oil is injected into mammary tissues of rats. Autoantibody production against connective tissue proteins is an immune response that is consistent with reports from women with silicone breast implants. The results also demonstrated pathological changes in animals that may result from the autoimmune response and that silicone gel can migrate to distant anatomical sites or localize at the implantation site. This work has been presented at The FDA Science Forum, The American Association of Immunology, and The American Association of Biochemistry and Molecular Biology.

The implication from these findings is that leaked oil from a breast implant via leaching or with rupture might provide stimulus for the production of autoantibodies in clinical patients. Therefore, OST scientists evaluated autoantibody levels (in blinded experiments) in serum samples from 150 patients representing four groups: women with silicone implants without connective tissue disease, women with silicone implants with connective tissue disease (CTD), women with connective disease but no implants, and healthy women volunteers. Results from these experiments show in a statistically significant manner that elevated autoantibodies to collagen type I, collagen type II and anti-DNA were detected in serum of patients with CTD, CTD + silicone implants, and silicone implants without CTD.

Using two different assays, autoantibodies to connective tissue proteins (e.g., collagen) and to DNA and intranuclear proteins have been detected in women with silicone breast implants. Historically, there is a strong correlation between anti-nuclear antibodies and clinical symptoms of some autoimmune diseases. OST has documented serum immune responses in these patients with the goal of enhancing the ability to predict the likelihood of immunotoxic symptoms occurring in the presence of implants, including breast prostheses. This work has been presented to the Institute of Medicine.

OST scientists are continuing to investigate these results by correlating this data to the clinical history of the patients. Researchers plan to determine the clinical significance of the data and to study a larger patient population well defined with regard to implants and autoimmune disease symptoms.

Molecular Biomarkers for New Approaches to Safety Assessment: Studies with Mercury

Key words: mercury, stress proteins, kidney, preclinical test method development

An important part of FDA’s mission is to facilitate the development, refinement, and validation of more sensitive and predictive preclinical methods in toxicology. One approach is to develop technologies that define molecular biomarkers of exposure and toxicity for ultimate use in preclinical safety evaluation and in risk assessment activities. Prior to acceptance as a standard protocol in preclinical and clinical safety assessment, these type of approaches must be carefully validated with traditional standards and understood mechanistically for risk assessment applications.

OST investigators are focusing on developing markers at the molecular level because such targets are usually the first responses induced by potentially hazardous materials. Ongoing studies are evaluating the "stress", or heat shock, protein response as a method that will more reliably predict potential adverse effects of device materials.

Mercury is a major constituent of dental amalgam and millions of teeth are filled annually with this material. Mercury, which accumulates in kidney and brain tissues, is one of many proteotoxicants that enhance the synthesis of heat shock proteins (hsps) as part of a cellular defense mechanism. Recently, in a study focused on expression of hsps in kidney in response to mercury injections, OST investigators determined the differential expression of hsps in rat renal cortex and medulla in response to mercuric chloride, a readily soluble form of mercury. The five hsps evaluated were hsp90; two members of the hsp70 family, the inducible hsp72 and the constitutive hsp73; hsp25, and a glucose-regulated protein (grp94). In whole kidney, mercury induced a time- and dose-related accumulation of hsp72 and grp94. Interestingly, hsp72 accumulation was predominantly localized in the cortex and not the medulla, while grp94 accumulated primarily in the medulla but not the cortex. Mercury is toxic primarily to the cells of the proximal tubules located in the cortex. These results demonstrate that hsp expression in rat kidney exhibits regional heterogeneity in response to mercury exposure. The study points out the need to fully understand the expression of particular biomarkers in various cell types and tissues if these new technologies are to be incorporated as surrogates for, or adjuncts to, existing traditional standard methods for safety assessment.

Particulate Effects on Immunologic Function

Key words: particles, cytokines, wear and degradation, macrophages, standards, research

Wear and corrosion of implanted medical devices, such as dental and orthopedic prostheses, may produce particulate debris which may lead to acute and chronic inflammatory responses in the host. In addition, polymeric particles, such as polytetrafluoroethylene (PTFE), may be injected directly into the patients for clinical indications. When particulates are present, the host monocytes/macrophages are activated and they synthesize or secrete mediators of inflammation, and phagocytize particles. In order to understand the mechanisms underlying the host immune response to particulates and device-associated infections, OST scientists have focused their studies on the impact of these particulates on macrophage function. Macrophages play a pivotal role in the body’s response to foreign bodies and they also interact with other cellular components in the immune system. OST developed an in vitro assay using established murine macrophages. This assay system was incorporated into an ASTM standard on the Biological Responses to Particles (F04.16.01). The inflammatory potential of particles prepared from medical device materials, such as PTFE, titanium oxide, hydroxyapatite (HA), polymethylmethacrylate (PMMA), SiO2 and fumed silica, polystyrene (PS), CdCl2, CdO, Al2O3 , and diamond particle was studied.

In the in vitro assay, murine macrophage cells were exposed to particles or chemicals with and without bacterial lipopolysaccharide (LPS), which is a component of bacterial cell walls that mimics bacterial infections. The cells were then evaluated for cytotoxicity, production of nitric oxide (NO), tumor necrosis factor-alpha (TNF-a ) and interleukin-6 (IL-6), both inflammatory cytokines. NO is induced by LPS and is critically important in eradicating microorganisms associated with infections, but it can also be harmful by causing tissue injury and vascular collapse. OST studies showed that minute amounts of LPS, which could be associated with a bacterial infection at the site of an implanted device, induced a significant amount of TNF-a , IL-6 and NO production by macrophages.

The in vitro studies showed that TNF-a was induced by PTFE, PMMA, TiO2, HA, SiO2, both forms of cadmium, and Al2O3 particles and by LPS. Polystyrene alone did not stimulate activity. PS in combination with LPS stimulated no activity significantly above the levels in response to LPS alone. Addition of particles to the macrophages did not stimulate NO production. However, addition of LPS to the particles affected the NO production. NO production increased in a dose-response manner with LPS plus PMMA, increased but not in a dose-dependent response with HA, and was inhibited by increasing concentrations of TiO2. Polystyrene particles in combination with LPS produced minimal and variable differences of NO compared to LPS alone.

The in vitro system showed that IL-6 is stimulated by LPS. Neither Al2O3 nor PS alone stimulated IL-6 production. IL-6 production was stimulated by Al2O3 in combination with LPS, but PS in combination with LPS did not stimulate above the LPS alone level.

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Thus far, the OST studies indicate the following: 1) this in vitro system measuring TNF-a , IL-6 and NO responses can detect differences in biological responses to particles; 2) no particle tested by OST thus far has induced NO whereas LPS is a potent stimulator; 3) some particles stimulate TNF-a production and some do not; 4) some particles enhance, some inhibit, and some have no effect on the stimulation of TNF-a and NO by macrophages in response to LPS; and 5) PS particles may serve as a negative control for evaluating the induction of these three biological responses.

Decontaminating Particles Exposed to Bacterial Lipopolysaccharde

Key words: particles, lipopolysaccharide, nitric oxide, macrophage, research

The presence of lipopolysaccharide (LPS) or endotoxin associated with implanted medical devices can stimulate fever in the host. Manufacturers must submit evidence that their sterilized implanted devices are below a given endotoxin level. The most commonly used assay to test for the presence of endotoxin is the Limulus Amebocyte Lysate (LAL) test. OST scientists have observed, using an in vitro murine macrophage assay, that LPS stimulates nitric oxide (NO) production. Clean, sterilized medical device particles examined thus far do not stimulate NO production, but certain particles that are contaminated with minute amounts of lipopolysaccharide (LPS, endotoxin) do stimulate NO production. Polymethylmethacrylate (PMMA) particles deliberately contaminated with minute amounts of LPS were assayed for the production of NO in the murine macrophage cell system. Treating particles deliberately contaminated with LPS with 70% ethanol at room temperature or higher for more than 24 hours followed by washing three times with endotoxin-free phosphate buffered saline reduced the level of detection of LPS in the in vitro cell system. LPS treated with 70% ethanol also did not stimulate NO production. Both the LAL test and the lack of LPS stimulation of NO production by murine macrophages show that 70% ethanol can inactivate LPS and may be a method to remove LPS from particles that are being tested for inflammatory potential.

http://lib.bioinfo.pl/meid:76594,

Am Rev Respir Dis. 1993 May ;147 (5):1299-302 8484647 [Cited: 4]

Silicone fluid-induced pulmonary embolism.

[My paper] Y M Chen , C C Lu , R P Perng

Silicone fluid injection for mammary augmentation is a well-known illegal procedure. It has been associated with many complications, including local tissue granulomatous reaction, chronic infection, and sclerosis, but pulmonary involvement in human beings has been documented in only six cases. We describe three more such cases of pulmonary embolism. These three patients were all female, young, and previously healthy. They received the procedures only for cosmetic reasons. Unfortunately, one of them died and another lived with the sequelae of pulmonary fibrosis. The mortality rate of the nine total patients with pulmonary embolism induced by silicone fluid, including our three cases, is 33%. Because of this high mortality rate and long-term sequelae of pulmonary fibrosis, no silicone fluid injection should be given for cosmetic reasons, especially in mammary augmentation in which a large volume of silicone fluid is more likely to be used, and the early use of corticosteroid therapy may be helpful.

see this, it is a safe implant.

Per: doctors, FDA, and drug companies

The FDA says about 6 percent get

necrosis, hum...300,000 people implants

in 2005, hum.......so, how many is that?

its huge ! now check this out, these are very safe: NOT !

Look at these lovely........" safe " ? ? ? ?.........saline implants:

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