Research Uncovers Key Step In Immune System Defense

July 9, 1999

(Medical Tribune) - In a step toward greater understanding of the underlying dynamics of immune-system-related diseases, researchers have discovered a key element in the immune system's response to viruses and other foreign invaders.

While scientists have long known that T cells orchestrate the immune response to foreign substances, or antigens, just how T cells "decide" whether a new antigen is present has been unclear.

Now, in a report in the July 9 issue of Science, researchers provide new details on the complex interplay between T cells and another immune-system player called the antigen-presenting cell. Antigen-presenting cells flag foreign invaders, helping T cells to recognize them and launch an attack.

Using a novel, moving model of the immune-system response, a team led by pathologist Michael L. Dustin of Washington University School of Medicine in St. Louis found that T cells and antigen-presenting cells must build a type of molecular bridge between them before the T cells can attack foreign invaders. The formation of this bridge, which the researchers call the immunological synapse, appears to tell T cells that they should respond to an antigen.

This discovery, according to Dustin, may lead to greater insight into T-cell activation, as well as better understanding of the "inappropriate immune responses" involved in a host of diseases.

For instance, Dustin noted, his team's research may lay the groundwork for discovering why the immune system sometimes misses foreign invaders such as cancerous tumor cells, and why it mistakenly attacks normal body tissue, as occurs with autoimmune diseases like juvenile diabetes and rheumatoid arthritis.

"Understanding [the immune response] at a molecular level is a powerful new tool in understanding inappropriate responses," Dustin said.

The system used by his team to observe the immunological synapse form may be a useful tool for enhancing researchers' knowledge of the immune system, according to Dustin. While scientists have used "killed" immune cells to create static images of their functions, Dustin's team was able to observe the cells operate in "real-time."

To do this, they created a model to simulate the function of antigen-presenting cells by constructing artificial cell membranes they then placed on a glass slide and viewed through real-time video imaging. The molecules of the membrane were color-coded to allow the researchers to better follow the interactions between the membranes and the molecules on the surface of the T cells.

During this interface, the researchers found that the cells' molecules rearranged themselves to form a synapse only when the T cells encountered a "high-quality antigen" - an antigen that in the body would likely elicit an immune-system attack. Whether this molecular arrangement occurs or not seems to control whether T cells attack an antigen or leave it alone.

"It was a huge surprise that there would be anything you can see with a microscope that is responsible for activating T cells," Dustin said. Most research in immunology, he noted, focuses on chemical interactions, which cannot be seen by the human eye.

Dustin predicted that real-time imaging will be become popular not only in researching the immune system, but also in studying other cell interactions, such as those of the nervous system. Dustin and his colleagues have used the system for several years, but he said this study is the first to use it to observe such complex cellular interplay.

The immune system comprises an array of cells, including different types of T cells, that perform specialized functions. So, Dustin noted, it is unknown whether all of these cells form synapses. He and his colleagues are studying other immune cells to help answer this question. The current study was funded in part by the National Institutes of Health and the Arthritis Foundation.

For more information on how the immune system functions, visit the

Web site of the National Institute of Allergy and Infectious Diseases at

Science (1999;285:221-26)

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Study Proposes Link Between Fetal Cells And Scleroderma LONDON, ENGLAND -- February 20, 1998 -- Results from a preliminary study, published in this week's issue of The Lancet, suggest that in some women scleroderma might be triggered by fetal cells which enter the women's blood stream during pregnancy and persist for years.

Scleroderma is an often severe, sometimes fatal autoimmune disease which predominately affects women.

Previous studies have shown that fetal cells, which commonly enter the mother's bloodstream during pregnancy, can still be detected in the mother's blood up to 27 years later. These fetal cells are immune progenitor cells, which have the potential to form a wide variety of immune cells. When such cells persist after a bone-marrow transplant, a reaction can occur called graft-versus-host-disease in which the donated immune cells attack the marrow recipient's body. This reaction bears similarities to scleroderma, raising the question whether scleroderma could be caused by persistent fetal cells.

To test this hypothesis, Dr. Lee Nelson from Seattle, WA., and colleagues collected blood from 40 women who had given birth to at least one son: 17 of the women had scleroderma; 16 were healthy; and seven were healthy sisters of patients with scleroderma. They tested the blood for the presence of male cells by looking for the presence of DNA from the male Y chromosome.

They found that the healthy women had on average only 0·38 male fetal cells per 16 mL. In contrast, the women with scleroderma had 11.1 male fetal cells per 16 mL. Interestingly, women with scleroderma were also likely to have given birth to children who had genetic similarities to their mothers, which would make it more likely that fetal cells could persist.

Although the findings are intriguing, the researchers admit that it is not clear how such a small number of cells could cause disease.

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Informed Consent: A Story of Personal Tragedy and Corporate Betrayal ... Inside the Silicone Breast Implant Crisis Thank you Kathy Nye for sending our way

The Journal of Business Strategy

Boston

Mar/Apr 1996

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Authors: Voss, Bristol

Volume: 17

Issue: 2

Start: Page 60

ISSN: 02756668

Subject Terms Chemical industry Breast implants Book reviews Classification Codes: 9190: US 9000: Short article 8640: Chemical industry, includes rubber & plastics. Geographic Names: US

Companies:

Company Name: Dow Corning Corp

DUNS: 00-535-3487

Company Name: Dow Chemical Co

Ticker: DOW

DUNS: 00-138-1581

Abstract:

Informed Consent: A Story of Personal Tragedy and Corporate Betrayal ... Inside the Silicone Breast Implant Crisis, by John A. Byrne, is reviewed. Copyright Faulkner & Gray, Inc. Mar/Apr 1996

Full Text:

Today's business authors certainly know the value of case studies as tools for proving their points-all of the books in this group are either one huge case study or a mix of dozens or more. Unfortunately, not all of the authors in this gathering understand the strategic relevance of the points they're trying to make. Perhaps the biggest disappointment is the case study profile on Microsoft (Microsoft Secrets) which-although orderly and logical-fails to prove that there is/was a strategy (let alone a symphony of strategies) driving one of the most successful corporations of the past decade. Frankly, the two authors miss the larger-and more timely-story on where the socalled strategic moves have tripped up Microsoft.

When authors do understand the strategy behind their stories, however, the books are brilliant. Informed Consent, for instance, is the most agonizingly thorough case study (outside of sealed courtroom documents) of how Dow Corning failed to live up to its avowed strategy of ethical and moral behavior. The fact that the book is so well written is paradoxically a handicap-the reader cannot absorb the horror as quickly as he can read about it.

One new twist in the case study format, which we hope to see more of, is the citation of fiction (novels, poems, plays, TV shows) as cases in point. This works surprisingly well with Company Man which, despite the fact that the point of the book seems as if it would be too simple to sustain a newspaper editorial is actually a fascinating, literary read. It could have run into a second volume without diluting the quality.

Informed Consent A story of Imeo personal tragedy and corporate betrayal...inside the silicone breast implant crisis, by John A. Byrne. Published: McGraw-Hill, New York.

Author's Credentials: Business Week writer who had access to unpublished first-person biography by Dow Corning executives.

Thesis: How compromise, consensus, and an inept general counsel created a corporate juggernaut that eclipsed the sum of the involved executives' values, ethics, and moral fiber which were, on an individual level, irreproachable.

Scope: Late 1950s to the present

File Under: Crisis management at its worst.

Reason to Buy/Read: On one level, the book's the "And the Band Played On" of silicone breast implants: Woven in with a brilliant chronological story is the litany of mistakes that everyonesurgeons, patients, FDA, foreign governments, scientific journals, the general press, Dow Chemical, and Corningmade. On another level, it's a portrait of how Dow Corning eclipsed every other 20th century corporation-including co-parent, Dow Chemical, which blithely strode through its own crises involving Napalm, Agent Orange, and dioxin-in arrogance.

Unintended Effect: Powerful argument for mandatory animal testing Placement in Your Life: Top of the pile on the bedstand

How to Read: On an empty stomach

Irresistible Miscellanea: In the 1960s, Dow pulled a silicone product for cleaning hands the night before the launch because a scientist called the marketing department with the news that the allegedly inert silicone shrank the lab monkey's testicles.

You will throw this book across the room if You were looking for any shred of evidence that would exonerate, excuse, or even explain Dow's corporate position.

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CFIDS ROAD MAP

A basic guide to help you on your journey through CFS and the jungle of information that's out there.

(AOL users: scroll to the bottom of this newsletter for AOL-friendly, clickable links.)

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FDA DOCUMENT OF THE DAY

From the Evidentiary Files of Breast Implant Litigation Thank you Rogene for converting image file to text for e-mail transmission.

Vol. 30, No 2/ BREAST IMPLANTS.

SUCCESSFUL TREATMENT OF SOME FIBROUS ENVELOPE CONTRACTURES AROUND BREAST IMPLANTS BROMLEY S. FEEMAM, M.D.

Houston, Texas

Note: references for this article were written between 1965 and 1970. References are not included because they were illegible.

Scar tissue contracture is inevitable around prostheses put in any soft tissues of the body, but is most evident around materials placed in (or just under) the subcutaneous tissue. Because of the necessarily thin flaps, this spherical scar contracture is quite apparent clinically in many patients who have had breast prostheses implanted after subcutaneous mastectomy, or for reconstruction after a radical or simple mastectomy.

The purposes of this paper are (1) to emphasize the 3-dimensional quality of the scar contracture around these implants, and (2) to describe a progressive clinical condition which can be recognized and relieved by circumferential section of the pseudocapsule, enlargement of the pocket, and reinsertion of a smaller implant. In addition, a syndrome of rapidly progressive contracture which results in skin ischemia and impending necrosis has been recognized in a small number of cases after subcutaneous mastectomy and insertion of prostheses.

PATHOGENESIS

After implantation of a foreign materials, normal healing is by the formation of a fibrous capsule. The form of the implanted material and the qualities of its surface will influence this reaction. The thickness of the encapsulation membrane is proportional to the chemical irritation of the implant, the mechanical irritation resulting from movement of it, and inflammation secondary to trauma, infection, and hemorrhage. The period of the progressive scar contracture may be dependent upon such factors as the following.

1.Excessive operative scarring.

2.Undrained postoperative seromata.

3.Persistent secretion caused by impurities of the surface of an improperly prepared prosthesis.

4.Massive fibroic scar from retained post-operative hematoma.

5.Late hemorrhage from severed minute vascular channels, opened by

excessive postoperative implant motion.

6.Intake of a fibrinogenic drug.

7.Chronic external trauma to a sympathectomized anesthetic flap.

Upon removal of these factors (and sometimes in spite of the continued presence of these irritants) the rate of contracture lessens or stops, and the size of the fibrous pocked becomes relatively stable. In the average case, active contracture diminishes or ceases after approximately 6 months, with maturation of lessening cellularity in the encircling membrane. It is during the cellular contractile phase, however, that the acute complications about which we are concerned occur. Not until after this should revision be attempted.

Toward the end of the initial short period of collagen organization, the develop of scar tissue tightens- diminishing or folding a compressible prosthesis, but contracting against a prosthesis of fixed volume to accentuate and project its edges and cause buckling, folding, and irregular distortions around it. The spherical force of this progressive fibroblastic contracture can form spheres from inserted hemispheres, hemi-ellipsoids, or truncated cones- for a sphere has the smallest surface area of any shape to contain a given volume (Fig. 1).

Caption Figure 1. The gradual changes that may occur from 3-dimensional contracture around a non-yielding gel prosthesis. A. The initial triangular or truncated cone form. B. Contraction of the fibrous capsule produces an ovoid form, with rounding of the base and flattening of the apes. C. Continued contraction and thickening of the capsule produces buckling superiorly, and a sphere. D. Opening the capsule and releasing the tension in all directions allows restoration to the original form.

Marked distortions in the positions of prostheses have occurred; they may be displaced laterally, inferiorly, or superiorly- despite long-term (3-week) immobilization by accurately placed dressings (and by the excellent fibrous attachments which may infiltrate the Dacron base of the Dow Corning prosthesis). The wide chest wall dissection necessary for subcutaneous mastectomy has not prevented these late contractures, distortions, lateral stretching of surface scars, and thinning of the skin; late skin erosion with terminal exposure of the implant may occur. A collapsible sac filled with liquid (a Simplast prostheses) has been contracted, folded, and distorted by a rather delicate encircling membrane- showing that the thickness of the capsule is no the sole cause of this syndrome (Fig. 2).

Caption Figure 2. Crumpling of an inflatable prosthesis, by capsular contracture. (left) mammogram made two years after augmentation with an Arion prosthesis filled with 142 cc Dextran and saline. (right) At operation, a delicate sac membrane was found compressing and folding the soft prosthesis.

In a few patients, vascular impairment of the inferior portion of the flap was followed some months after surgery by slow, ischemic skin atrophy. In others, subsurface scarring, dependency, and brassiere pressure has let to stasis and venous thrombosis- making the breasts more vulnerable to trauma and resulting in skin erosion with implant exposure.

The skin of the lower breast and areola is nourished by vessels running through the breast parenchyma; the vascular anastomoes below the areola are frequently incomplete in this site. During subcutancous mastectomy, in addition to interrupting these major vessels which course from the chest wall through the breast to the skin, the inferior vascular supply is also severed by the submammary incision. In all the patients we have seen with delayed or late ischemic necrosis, the area of vascular change and skin atrophy was localized to the central inferior sector of the breast-just below the areola.

In earlier patients undergoing subcutaneous mastectomy, sponge prostheses were used for the augmentation and late skin erosion and implant exposure did not occur, fur the volume of the compressible sponge implants diminished with the increased pressure. Late skin ischemia and necrosis have been a problem only since the advent of the gel-filled silicone prostheses- a non-compressible gel of fixed volume encased in a mobile, but firm, envelope. The encircling pseudocapsule becomes firmly attached to the dermis of the skin and compresses around the prosthesis, to thin the subcutaneous tissue and impovrish the borderline blood supply of the skin. Such atrophic skin is then easily injured by minor trauma such as sunburn, heat, and even light abrasion by a brassiere.

CLINICAL TYPES OF CONTRACTURES

The patients requ8iring operative release of their contracture have been segregated into 3 categories.

A.Early, mild contractures reach an arrested or plateau phase some 3 to 6 months after operation. Most of these patients have thin-walled, small breasts; they may develop moderate irregularities in shape or position. They can be re-examined from month to month, and can be offered an elective surgical release after a year or more. Into this class with fall those few simple augmentation mammoplasties which develop clinical contractures.

B.Slowly progressive contractures, continuing over a year. Patients who have had total reconstruction of the

C.Breasts after a radical or simple mastectomy may fall into this class. In addition, several patients subjected to subcutaneous mastectomy and augmentation - after a relatively stormy postoperative course (seroma, hematoma) developed progressive, deep changes which continued for a year or more (Fig. 3, 4).

Caption Figure 3 .Severe contracture associated with daily use of a fibrogenic drug for several years. (upper left) Four months after subcutaneous mastectomy and immediate placement of implants, the breasts became displaced laterally and distorted. (above right)The revised pocked on one side, prior to replacement of the implant with a smaller prostheses. (below left) Appearance at the conclusion of this operation, (below right) Six months later there was recurrent contracture of the capsule and displacement of the breast. A third operation was done later in which the implant was removed, the opening through the capsule was enlarged circumferentially, and the small implant was replaced. This was followed by lasting improvement.

Caption Figure 4. Photomicorgraph of a biopsy form the capsule in the patient shown in Figure 3. This cellularity at the second operation indicates that the process was still active then, mitigating against success at that time.

A.The acute fulminating type may return within 3 to 4 months, because of skin changes, for treatment of an impending erosion, or because of exposure of the implants. These changes have occurred only in patients with small breasts who were subjected to a subcutaneous mastectomy. Despite a tension-free augmentation and a relatively foreign postoperative course, they developed these complications in an acute and fulminating manner (Fig 5).

Caption Figure 5. Progressive capsular contracture, necessitating emergency surgery. (left) Two months after an uneventful subcutaneous mastectomy and insertion of a small gel-prosthesis, atrophic changes became apparent in the overlying skin. Surgery was strongly urged, but refused by the patient at this time (right) Some 5 1/2 months after the operation she has skin necrosis in the classic area, caused by brassiere pressure over thinned-out cover. She required immediate excision of the thinned area, revision of the scar and insertion of smaller implants.

Constant checking is essential. The patient cannot be permitted to merely observe herself -for grotesque contractures have been found, even after Teflon disks alone have been inserted (for space retainers, preliminary to a later augmentation).

TREATMENT

The progressive tension created by the scar can be relieved by surgically creating a larger pocket, by the insertion of a smaller, less irritating, or more pliable prosthesis, or by both.

Through the submammary incision scar the pseudocapsuleis incised, and the implant is exposed. In most patients, the lateral medial walls of the fibrous sac can easily be dissected free and then incised along the base to the superior curve (Fig. 6). A lighted narrow Harrington (of Deaver) retractor exposes the superior curve; this is freed and also split along the line of the base. Dissection circumferentially permits blunt freeing of the tissues for an additional one inch on all sides -laterally, medially and superiorly, as well as on the inferior flap-leaving the fibrous dome and base intact (Fig. 6). If the initial size of the implant has been modest, nothing more is necessary and the wound is closed.

Caption Figure 6. To enlarge the pectoral pocket in all directions, one goes through the old incision area and the sac to the surface of the implant. The hemispheric dome of the matured sac is then loose from the flat base all the way around, allowing expansion in all directions. A decision is made the whether to leave the original implant or to replace it with a smaller one.

If the skin shows changes, however, or if the implant is too gross, the Dacron patches are incised and the prosthesis is removed. A small implant is then inserted.

Removal of a prosthesis covering, leaving the gel mass, has been done-to try to prevent, or lessen the incidence of continued contracture, and to give a smaller mass. One might question the use here of such a highly cohesive material as silicone gel which, because of its 3 dimensional linkage, will "ball" without a restrictive envelope. When implanted, both experimentally and clinically, it has resulted in the formation of spheres encased in fibrous shells. Despite this tendency, this cohesive gel (with the limiting membrane removed) was reinserted into an enlarged pocket in 4 totally reconstructed breasts; no further contracture occurred during the periods of one to 3 years (Figs 7, 8).

Caption Figure 7. Reconstruction of one breast, 7 years after a radical mastectomy, (above left) Preoperative, (above right) One year after reconstruction with a gel prostheses, plus areola and nipple grafts from the opposite breast. Note the lateral retraction and distortion of the reconstructed breast. (center left) At 18 months, the sac was incised and the prosthesis bulged through the wound immediately, under much tension. (center right) The prostheses was removed and the sac lining can be seen just prior to incising it all around to enlarge the pocket. (below left) The bag of the silicone prostheses was opened, and the gel from it was poured into the pectoral pocket. (below right) Results shown one month later.

After augmentation mammaplasties, 6 breasts were revised in a like manner.

TIMING OF TREATMENT

In general, one should wait until after the period of rapidly progressive contracture before an elective revision is undertaken - either for replacement with a smaller prosthesis, or to enlarge the pocket (Fig 4.)

RESULTS

Thirty-five patients have had this pectoral pocket release procedure, or some similar reoperation. Fourteen were done after subcutaneous mastectomies (8 percent cases, 6 referred), 6 were done after breast reconstructions with plastic implants following simple or radical mastectomies, and 15 were done after simple breast augmentations (these were reoperated for relatively minor complications).

There were only two significant recurrances of the contracture; one was thought to be caused by the continued and excessive use of a fibrogenic drug, the other by an unrecognized rib cage abnormality (Table 1)

SUMMARY

Most the deformities developing weeks or months after the insertion of breast prostheses are due to progressive tension produced by shrinking of the fibrous capsule which forms around any implanted prostheses. Deformities may appear from buckled or rolled edges, or the prosthesis may be displaced in any direction. There may be thinning or discoloration of the skin over a prominent area of the implant, with impending extrusion of the implant. The clinical types of this capsular contracture are discussed.

Treatment usually consists of circumferential incision of the fibrous sac, separating it into a base and a dome. At times, one also removed the original implant and substitutes a smaller one. On a few occasions, with the gel-filled sac type of implant, the sac has been removed and the gel left in the new cavity. Treatment has been successful in 33 out of 35 cases.

FDA000053946

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OTHER SILICONE RELATED RESOURCES ARE AVAILABLE THROUGH THE SILICONE WEBRING

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WHERE THERE'S SMOKE THERE'S FIRE ~ On The Net

The following websites have the "Where There's Smoke There's Fire" documents:

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FOR AOL MEMBERS OR OTHERS, WORKING WITH ON-LINE SERVICES NOT EASILY ACCOMMODATING THE FORMAT OF THESE NEWSLETTERS, YOU MAY ACCESS THEM FROM THE CANADIAN CONNECTION WEBSITE AT THE HYPERLINK BELOW. TONY & MICHELINE LAMBERT HAVE GRACIOUSLY ARCHIVED THEM FOR US.

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INSPIRATIONAL

Sent by Ruby Rahn. Beautiful Material Ruby, thanks for sending it.