Sunday, July 31, 2011

Chromium 3 results in permanent modification to DNA in MoM hip? (2 of 6.) What does this mean?

  I would like to understand what it means when they say that "direct binding of Cr3 to DNA is well documented" and why this matters to us as patients.

  • Wolf et al 1989
  • Landon et al 2004
  • Bacon et al 1983
  • Martnett 1999
  • Hartwig et al 2003
I will explore this in a series of 6 posts, this being post two  which is a brief review of post 8 Review of the Cell biology surrounding metal on metal hips (8 of x in a series) .

First, I wanted to mention that the Depuy hip contains Chromium 3.  It is my understanding that the Chromium 3 is not oxidized from Chromium 6.  I will double check on that because I have been repeatedly told that Chromium 3 is a non carcinogen while Chromium 6 is a carcinogen.

The most common forms of chromium are trivalent (chromium 3) and hexavalent (chromium 6); in its trivalent state, the chromium atom is missing three electrons, and in its hexavalent state, it is missing six electrons. In the environment, chromium usually exists in the trivalent form. It is possible for one form to change into the other when chemical conditions are right. Although the trivalent form of chromium shows very low toxicity, both the federal and California EPA have designated hexavalent chromium a carcinogen. (http://www.chromium6.org/)

There is substantial evidence from laboratory studies that chromium 6 can damage DNA and is a mutagen.

Since the prolonged exposure to chromium results in, allowing the chromium 6 to get accumulate in the cells and then move to blood stream all over the body, hence, you should take necessary precautions for avoiding continuous exposure to the chromium 6. It also results in kidney as well as liver damage, since it attempt to filter the toxins that are present in your body, which gets accumulated in your kidney and liver and results in kidney or liver failure.

There is concern whether in vivo corrosion of chromium-cobalt alloys releases ions containing trivalent [Cr(III)] or hexavalent [Cr(VI)] chromium. The question arises from indications that Cr(VI) is far more biologically active than Cr(III).

Here is MY  question: If it is possible for one form to change into the other when chemical conditions are right is there or should there be a concern about this "morphing" of one form of chromium to another?   Simiarly, I am concerned about this statement by  one of the law firms:  "Our research indicates that hexavalent chromium is the type of chromium being released by the ASR Acetabular system; it degrades in the body into trivalent chromium, or Chromium (III). Anywhere from 18-30% of a typical metal-on-metal implant is composed of chromium; we do not have current numbers on the amount of chromium included in the DePuy hip implant. (http://www.sullolaw.com/Article/chromiumpoisoning.html)


Well, this is exactly the issue addressed in this series of articles.  If this statement  is true, and I have no idea whether it is or isn't, the issue of hexavalent chromium is back on the table.  This research has lead me to the question:  Is the chromium in the depuy hip hexavalant which  is immediately oxidized to trivalant or are they claiming that the chromium is trivalent in its original state in the hip?  I have no clue.  This should be clarified by Depuy.  I can tell you that most of the articles on this topic address chromium oxidation interchangeably with Metal on Metal hips.

What does Wolf Say?

Carcinogenesis. 1989 Apr;10(4):655-9.

Molecular interaction of different chromium species with nucleotides and nucleic acids.

Source

Institut fur Arbeitsphysiologie, Dortmund, FRG.

Abstract

The interaction of chromium(III) and chromium(VI) with the phosphate groups of di- and triphosphate nucleotides were examined by 31P-NMR spectroscopy. Chemical shifts of the phosphate groups, indicating the formation of Cr-nucleotide complexes, could only be detected with Cr(III). When Cr(III) was generated from Cr(VI) by reduction with an excess of glutathione, nearly the same chemical shifts could be observed. This indicates that glutathione is not capable of trapping Cr(VI) by reduction with subsequent formation of stable Cr-GSH complexes, thus preventing the binding of chromium to important target molecules as DNA or nucleotides. Using radioactively-labelled chromium no 51Cr(VI) bound to any nucleic acid, whereas 51Cr(III) bound in increasing order to poly(A).poly(U), calf thymus DNA and poly(G).poly(C). Furthermore, the melting temperature of nucleic acids increased in the same order only in the presence of Cr(III). Possible genotoxic consequences in vivo of the presented data in vitro concerning the binding of Cr(III) to sensitive molecular targets are discussed in detail.

[ Well, I surely don;t understand all of the intracacises of this but what I gather from this is that Cr 3 binding to DNA is well documented.]

Tomorrow, I will look at Bacon and Marnett.

Saturday, July 30, 2011

Research questions re Chromium 3

Hey guys, just wanted to make a point prior to my proceeding to the 5 subsequent posts.  I remember a conversation I had with one of my surgical  consults when he was reviewing my case.  He asked me two questions:

(1) We don't want to create mass hysteria do we [over these kinds of questions?]
(2) You don' think Depuy invented a hip with the thought in mind to harm anyone do you?

The obvious answer from any educated person would be unequivocally no to both of the above BUT...

If no one can answer  questions because we just don't know the answers,  we must to continue to ask them until some research funds are allocated to answer the questions.  When are adequate research dollars going to be allocated to deal with these carcinogenic issues?  Why don't we have key research teams around the country working on these issues now?  Why are most of the articles I will be looking at in the next 5 posts date from journal articles that are referenced   from 1983 -2004? 1983....this is stuff from 30 years ago?  How can the most recent information on intracellular effects re these metal ions come from something published from 7 years ago?

All mind boggling isn't it?

I have been all over the country consulting with the best experts in this matter and my local surgeon had the best synopsis of this whole thing re the hips:  "Its all murky."  I have never seen a better synopsis of what we know about the implications of the MOM issue. 

I think there are quite a bit of interesting seeds that have been sown in the research so we as a patients must insist that this research be funded. As a patient, it is not comforting  to have no solid conclusions as to what is in store for me long term as a result of this metal issue.  I can assure you of one thing, after having gone through volumes of studies....no one knows.  No medical professional will tell you that there are no long term issues with MOM implants....because they just don't know.

You can count on me to continue to ask questions until someone knows the answers.

I am the first person who will stand up and say this Depuy hip changed my quality of life when I had it put in 5 years ago so I will be forever grateful for being given the opportunity to walk normally again. I think I said that is my first post.  It may be that I have been given that opportunity with a set of unidentified risks.  My search to mitigate those risks going forward continues.    Had I known these risks, I may have looked at alternate devices.  Hindsight is always 20/20.

Please look at the inquires into the carcinogenic issues, DNA changes etc as that; inquiries into what long term systemic effects we may have in store for us.

Connie

Chromium 3 results in permanent modification to DNA in MoM hips. (1 of 6.) What does this mean?

I wanted to explore 5 references from the prior series re the effect the Chromium 3  (contained in the Depuy hip and is presumably the non toxic form of Chromium) has on making permanent modification of the genetic material of the DNA hence represents the first step in carcinogenesis.  I don't believe I have reviewed these references before. 

This does not mean the Chromium 3 causes cancer!   It doesn't mean that it doesn't cause cancer either.  It is my understanding that the meaning of all of this is unclear in terms of its long term effects.

I would like to  understand what it means when they say that "direct binding of Cr3 to DNA is well documented"  and why this matters to us as patients.
  • Wolf et al 1989
  • Landon et al 2004
  • Bacon et al 1983
  • Martnett 1999
  • Hartwig et al 2003
I will explore this in a series of 6 posts, this being post one  which is a brief review of  post 8 Review of the Cell biology surrounding metal on metal hips (8 of x in a series)  .

5. Permanent modification of genetic material resulting from this "oxidative damage" [From the MOM hips] represents the first step in mutagenesis*, carcinogenesis** and ageing.

*mutagenesis-process by which the genetic information of an organism is changed.
**carcinogenesis-is literally the creation of cancer.

6. Although no evidence has been found for direct binding of Co2 to DNA, direct binding of Cr3 to DNA is well documented (Wolf et al, 1989)

7. Two main processes exist to correct DNA aberrations and to restore the integrity of the genome.

8. Both of these repair mechanisms are inhibited with Cr3.

9. Landon investigated changes in metal ion levels and chromosome aberrations in patients within 2 years of receiving Metal on Metal hips. The authors noted an increase in translocations* and aneuploidy** in peripheral blood lymphocytes at 6, 12 and 24 months after surgery.

*Translocations-In genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer.

**aneuploidy- is an abnormal number of chromosomes, and is a type of chromosome abnormality. An extra or missing chromosome is a common cause of genetic disorders (birth defects). Some cancer cells also have abnormal numbers of chromosomes.

I will look at each of the 5 journal references in the next 5 posts.

Connie

Thursday, July 28, 2011

Report could sway FDA device review process


WASHINGTON | Tue Jul 26, 2011 1:40pm EDT

WASHINGTON (Reuters) - The Institute of Medicine is poised to advise the U.S. drug regulator how it can refine its medical device approval process to get products to market quickly while protecting patients.

The Food and Drug Administration requested the IOM report as part of Commissioner Margaret Hamburg's vow to improve the FDA's device unit, an area dogged by high staff turnover and funding woes.

Friday's report by the influential nonprofit organization is expected to address some of the more contentious changes proposed by FDA to the accelerated device approval process, known as the 510(k) program.

Critics say the accelerated 510(k) process is too widely used and leads to inadequate testing for some risky devices, but it is defended by industry as necessary to speed technologies to patients.

Nearly a year ago the FDA proposed changes to the program, including the possibility of creating a new category of more risky devices that would require more data to win approval.

This new category is among the issues the IOM report is expected to address.

"Potentially it could have a big impact on how things will be changed," said Dr. Gregory Curfman, executive editor of The New England Journal of Medicine, of the IOM's report.

Medical devices range from simple bandages to complex implants such as pacemakers, stents and artificial knees. The largest medical-device makers include Medtronic Inc , Johnson & Johnson , Boston Scientific Corp and Abbott Laboratories Inc .

The 510(k) program allows medical devices to get to market faster if they are "substantially equivalent" to an existing product. Critics say this can allow unsafe products to reach the market. Most new medical devices - about 3,000 each year - are cleared through the program.

High-profile incidents include a massive recall last year of artificial hips by Johnson & Johnson's DePuy unit. Some 93,000 patients worldwide had that line of hip implant.

Some health policy organizations were critical of the FDA for not moving sooner to make changes to the device approval process.

"Let me say that the whole process is illogical, because the FDA knows best what they need to do," said Diana Zuckerman, president of the National Research Center for Women & Families. "And in some kind of ideal world the FDA would have come out with these proposals and implemented them."

Hamburg said on Monday that the agency should do more work to explain the approval process, especially to small device manufacturers.

"I think there's a lot to be done," she said in a speech at the office of Public Citizen, the consumer advocacy group. "I think the FDA has a responsibility to take a serious look at how we're organized to do business."

Wednesday, July 27, 2011

Review of the Cell biology surrounding metal on metal hips (9 of 9 in a series)

The material for this series of posts is sourced through the the following journal article:

Acta Orthop. 2008 Dec;79(6):734-47.
Metal-on-metal hip resurfacing arthroplasty: a review of periprosthetic biological reactions.
Mabilleau G, Kwon YM, Pandit H, Murray DW, Sabokbar A.
Conclusions from this series of 9 posts:

1. Although elevated levels of metal ions in the synovial fluid and in the peripheral blood after MoM atheroplasty are a common finding, the importance of these observations remain unclear.

2. These adverse biological responses to the metal ions produced can be local or systemic,

3.  Clinical cases of local tissue reactions (near the hip joint) are being increasingly reported.

4.  The precise biological pathway that leads to these localized effect of metal particles remain unknown.
 
5.  The high concentration of metal particles confined within the joint space may lead to activation of the T lymphocytes.

6.  In turn, this may may affect other local cell populations (as we discussed in the prior posts.)

7.  The individual biological response to the presence of wear debris appears to vary.

8.  This may reflect a different toxic-effect threshold or immunological intolerance.

9.  In some patients, the T cell-mediated interplay may lead to adverse clinical outcomes such as painful soft-tissue masses or other issues.

10.  The concerns about the unknown risks of  long-term exposure to metal debris remain.

11.  As the latency time of the metal on metal hip could be as long as 20 years, one can speculate that there may be development of tumors in response to excessive metal particles and metal ion production in these cases

12.  This highlights the importance of long-term clinical follow up and cellular research into the biological mechanisms involved in the pathogenesis of metal wear particle -induced adverse biological reactions.

[This concludes the series on these posts other than sharing some of the key papers referenced in this document...at least insofar as I am concerned in the SYSTEMIC (other areas of the body away from the joint)  arena vs the LOCALIZED (near the joint) arena.  I will share those with you in the next posts.]

Tuesday, July 26, 2011

Review of the Cell biology surrounding metal on metal hips (8 of x in a series)

The material for this series of posts  is sourced through the the following journal article:

Acta Orthop. 2008 Dec;79(6):734-47.
Metal-on-metal hip resurfacing arthroplasty: a review of periprosthetic biological reactions.
Mabilleau G, Kwon YM, Pandit H, Murray DW, Sabokbar A.

Metal-induced intracellular effects- metal of concern is Cobalt and Chromium 3 found in the Depuy hip.

1. Reactions with metal ions can lead to generation of free radicals which can, in turn, cause cellular dysfunction.

2.  Inside the cells, Chromium( Cr)6 is oxidized to Cr 3 in a series of steps that generate free radicals.
(Chromium 6 -the toxic form of Chromium-  Chromium 3, -purportedly the non toxic form of Chromium found in the Depuy hip.-

3.  Cobalt (Co) ions can also lead to the generation of free radicals.

4.  Free radicals can react with DNA and induce damage to the building blocks of DNA.

5.  Permanent modification of genetic material resulting from this "oxidative damage" represents the first step in mutagenesis*, carcinogenesis** and ageing.

*mutagenesis-process by which the genetic information of an organism is changed.
**carcinogenesis-is literally the creation of cancer.

6.  Although no evidence has been found for direct binding of Co2 to DNA, direct binding of Cr3 to DNA is well documented (Wolf et al, 1989)

7.  Two main processes exist to correct DNA aberrations and to restore the integrity of the genome.

8. Both of these repair mechanisms are inhibited.

9.  Landon investigated changes in metal ion levels and chromosome aberrations in patients within 2 years  of receiving Metal on Metal hips.  The authors noted an increase in translocations* and aneuploidy** in peripheral blood lymphocytes at 6, 12 and 24 months after surgery.

*Translocations-In genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer.

**aneuploidy- is an abnormal number of chromosomes, and is a type of chromosome abnormality. An extra or missing chromosome is a common cause of genetic disorders (birth defects). Some cancer cells also have abnormal numbers of chromosomes.

10.  The authors however, did not find any statistically significant correlations between chromosomal translocation indices and Co or Cr concentrations in whole blood.

[  connie:  so what about the abnormal number of chromosomes?]

conclusions tomorrow....

Monday, July 25, 2011

Review of the Cell biology surrounding metal on metal hips (7 of x in a series)

The material for this series of posts  are sourced through the the following journal article:

Acta Orthop. 2008 Dec;79(6):734-47.
Metal-on-metal hip resurfacing arthroplasty: a review of periprosthetic biological reactions.
Mabilleau G, Kwon YM, Pandit H, Murray DW, Sabokbar A.

Metal ions  in cells (metal transport)

1. Microparticles of  Cobalt (Co) and  Chromium (Cr) can be phaogcytosed* by cells

*phagocytsis- is the cellular process of engulfing solid particles by the cell membrane.  It is a major mechanism used to remove pathogens and cell debris

2.  The metal particles are exposed to a series of oxidative mechanisms designed to destroy a foreign body which leads to to the generation of metal ions and free radicals.

3.  It is still unclear as to how the metal ions can be released from the lysosome*.

*lysosome-cellular organelles that contain acidic enzymes to break down waste materials and cellular debris.

4.  It has been suggested that nanoparticles may be taken into the cells by a well-characterized pathway used by cells to absorb nutrients.

5.  Corrosion is the main degradation process of metals.

6.  Metals become  protected against corrosion by the formation of an oxide layer at the surface however, under certain conditions, the oxide layer can be removed, allowing the surface of the metal to come into direct contact with the corrosive compounds of the biological fluids.

7.  Metal ions may also enter cells directly by different pathways such as using an ion transporter or by using specific metal ion binding proteins.

8.  Cr ions cross the cell membrane.

9.  Within the cell, Cr6 undergoes rapid metabolic reduction via acid and other chemicals.

10.  Although Cr3 is known to exist, it is unclear how it can cross the cell membrane.

[ have blogged extensively on the confusion surrounding Chromium 6 (the toxic form of Chromium) and Chromium 3, (purportedly the non toxic form of Chromium found in the Depuy hip.)    As mentioned previously, Chromium seems to have the ability to oxidize from 3 to 6 and vice versa. Thus far, reported cases of this oxidation have occurred only under specific industrial conditions however that is not what this document seems to suggest. see next post on this subject.]

Sunday, July 24, 2011

Review of the Cell biology surrounding metal on metal hips (6 of x in a series)

In the last few posts, we examined the effects of metal particles on bone cells.  In the last post, we talked about Ostoblasts (cells that make the bone) and how the metal particles adversely affect the functionality of those cells.
 
The material for these articles are sourced through the the following journal article:
 
Acta Orthop. 2008 Dec;79(6):734-47.
Metal-on-metal hip resurfacing arthroplasty: a review of periprosthetic biological reactions.
Mabilleau G, Kwon YM, Pandit H, Murray DW, Sabokbar A.


Osteoclasts (not to be confused with Osteopblasts): are a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone (organic dry weight is 90% collagen). This process is known as bone resorption

(1) It has been shown that Co (cobalt) ions induced the death of osteoclast precursors after several weeks of co-culture with bone marrow cells.

(2) Studies have been conducted on rabbits bone marrow with the results showing that cell death did not occur but once the metal  was introduced after 4 days of Co ions, a decrease in the size of the mature osteoclasts.

The next posts will address the metal ions in cells.  We will look at the metal transport in cells and the metal-induced intracellular effects to show how the  permanent change in the genetic material (DNA) occurs which represents the first step in the carcinogenesis.

Saturday, July 23, 2011

Review of the Cell biology surrounding metal on metal hips (5 of x in a series)

Acta Orthop. 2008 Dec;79(6):734-47.
Metal-on-metal hip resurfacing arthroplasty: a review of periprosthetic biological reactions.
Mabilleau G, Kwon YM, Pandit H, Murray DW, Sabokbar A.

Osteoblasts-cells that are responsible for bone formation

1.  Metal ions can influence the biology of osteoblasts

2.  Exposure to metal ions can result in a dysregulation of osteoblasts and osteoblast-like cells.

3.  Although the metal ion concentrations within the bone in vivo  has not been established, exposure of ostoblasts to /Cobalt particles at concentrations of of 100ug/L or higher, leads to the development of certain changes in the cell (vacuole creation.)

4.  Cr and Co ions are toxic for osteoblasts leading to markedly reduced activity with certain molecules that prevent organic molecules from passing through the cell membrane.

5.  A decrease in protein, DNA, and RNA synthesis has been shown with Co and Cr ions.

6.  Certain proteins are important for the calcification of bone matrix.

7.  These protiens  are synthesized by ostoblasts and released into the extracellular matrix.

8.  Cr and Co inhibit the release of ostocalcin into the bone matrix contributing to the delay in mineralization of the bone tissue following exposure to the metal.

Friday, July 22, 2011

The Pinnacle Hip recommended for my revision surgery?

Just a brief diversion from the systemic issues for a day. I was  shocked when my surgeon recommeded using the Pinnacle hip for my revision.  As far as I knew from the press, the Pinnacle hip was about to be recalled!  I was perplexed so I started to look into this hip. 

(I had to revise this post on the following day 7/23 to clarify these numbers.)

(1) Depuy makes the Pinnacle hip as well as the ASR that was recalled.  I was not too happy about that recomendation as  I would have  preferred to stay away from the Depuy products for now.  I am pretty open minded so I began looking into this Pinnacle hip.  If I am to go to my surgeon with a NO Pinnacle,  my facts better be in order.

(2)  There are many types of Pinnacle hips.  They are componetized unlike the monoblock (one piece) ASR.   That means the surgeon has an option as to  to place metal-on-metal, metal on ceramic,  metal on plastic,  metal on Poly, ceramic on poly etc.  My surgeon recommend metal on poly. I am going to ask about the ceramic on poly.

 So my first question was what Pinnacle device is the problem in the press?    It seems as though the culprit (if there is one) is the Pinnacle 36 MM Ultamet metal-on metal which has been "reported to be failing at high rates."   Well, I can surely tell you that there is no way I would  put another Metal on metal device in my hip....regardless of who makes it anyway.

(3) I started reviewing  the history of the Pinnacle line
  • Released to the market in 2001 so its been on the market for 10 years.
  • 1 million patients have been implanted with Pinnacles since they were released worldwide
  • While Depuy reports a clinical success rate of 99.9% reported at 5 years, I don't know what that means for the individual product lines. 
  • Is that success rate for all hips in the pinnacle line? 
  • What hip line does this rate refer to?
  • Have there been any studies by product line? 
(4) I wanted to review the FDA complaints because I had seen this data on the ASR prior to its recall.  So, I decided to compare the complaints between the ASR recalled hip prior to their recall and the complaints for the Pinnacle hip, again with the understanding that I don't know what model of Pinnacle the complaints are coupled with but assume they are the MoM mentioned earlier.

 Nearly 1300 adverse reports have been filed with the FDA for the Pinnacle hip implants since 2001. In 2010, 545 adverse events were filed (40% of the total).. Most of the reports were filed from 2005-2010.  I don't know which Pinnacle hip implant was involved though.

 625 adverse reports were filed to the FDA  with the  Depuy ASR between 2006 and 2009.

It seems that in each case, relative to the number of hip implants each had on the market, the incident numbers reported to FDA seem to be small. 

Depuy ASR:  625 problem reports to the FDA over 5 years (US) to 93K on the market world wide (37K in the US.) I would assume the problem reports are US only so it looks like problem complaints  totaled about 2% in the US market if my math is right.

Depuy Pinnacle: 1300 problem reports since they have been placed on the market (US) to 1 million on the market world wide.  (150K Pinnacles  in the US have been placed but I will have to check on those numbers.  If 150k is right for the US market, the complaint rate is  less than 1% over 10 years.

90%  of the Depuy ASR hip complaints required revision.  Not sure about the Pinnacles.

I think I would like to see the poster presentation from the AAOS conference in 2007 which makes the claim about the clinical success rate of the Pinnacles over 5 years. I wonder what configuration of the hip was being studied?

I would like to  see more information on these Pinnacle devices but I am not as negative as I was when I first heard this recommendation. Seems like it is  a device worth considering unless someone else out there has additional information?

I have gone back to reivew the press reports and found that most of the reports are from litigators. Humm?  I don;t understand how the problem reports for the Pinnacles over 10 years were relatively low and now there seems to be a plethora of reports (40% of the total incidents to the FDA.)  This doesn't make sense.  I will check to see if I can get a confirmation on my understanding of these numbers. 

Connie








 

Thursday, July 21, 2011

Review of the Cell biology surrounding metal on metal hips (4 of x in a series)

Acta Orthop. 2008 Dec;79(6):734-47.
Metal-on-metal hip resurfacing arthroplasty: a review of periprosthetic biological reactions.
Mabilleau G, Kwon YM, Pandit H, Murray DW, Sabokbar A.

Metal- Induced Immune Responce Section (in my words and in short posts as this is rather complicated to follow but interesting and will give you a sense of how this metal causes issues in the body.)

1. It has been documented that the size, shape , number and nature of the particles released from the surfaces of the hip prosthesis are responsible for the type and extent of the biological response.

2.  Polyethylene particles have been shown to elicit a foreign-body, granulomatous (mass of immune cells that forms when the immune system attempts to wall off substances that it perceives as foreign but is unable to eliminate like metal)  response stimulating infection, which consists mostly of :
3.  Chromium and cobalt (contained in the metal on metal hips) have an effect on cells that is different to that of polyethylene and most other biomaterial.

4.  The metal particals are often phagocytosed (engulfed and then digested) by macrophages (white cells that digest debris-like metal.)

5.  Once phagocytosed, Chromium and cobalt particles can be toxic and rapidly kill the cells.  This is likely because they corrode quickly within the cells due to the acidic environment in the cell and then release ions in high concentrations within the cells leading to toxicity.

6.  The cells then lyse (breaking down of the cell), releasing the particles and cell contents to cause further damage.

7.  There is recent evidence that the metal particles, which are orders of magnitude smaller than polyethylene particles, induce an acquired or antigen-specific immune response (involves production of an antibody by the immune system) driven by T lymphocytes.

(T cells (Thymus cells) and B cells (bone cells) are the major cellular components of the adaptive immune response. T cells are involved in cell-mediated immunity whereas B cells are primarily responsible for humoral immunity (relating to antibodies). The function of T cells and B cells is to recognize specific “non-self” antigens, during a process known as antigen presentation. Once they have identified an invader, the cells generate specific responses that are tailored to maximally eliminate specific pathogens or pathogen infected cells. B cells respond to pathogens by producing large quantities of antibodies which then neutralize foreign objects like bacteria and viruses. In response to pathogens some T cells, called T helper cells, produce cytokines that direct the immune response while other T cells, called cytotoxic T cells, produce toxic granules that contain powerful enzymes which induce the death of pathogen infected cells. Following activation, B cells and T cells leave a lasting legacy of the antigens they have encountered, in the form of memory cells. Throughout the lifetime of an animal these memory cells will “remember” each specific pathogen encountered, and are able to mount a strong and rapid response if the pathogen is detected again.)

8.  It is likely that the continuous release of metal particles from the meal-on-metal hips and their local accumulation within the joint space, facilitates sensitization with a consequent cell-mediated immunological response.

9.  That response in some patients may lead to two things:
  • local reaction around the joint (aka osteolysis)
  • [Systemic reaction?] whereby the metal is transported to other areas of the body other than the hip joint.
The article reference is provided for your reference as I am not a doctor, nor a scientist.    In order to follow this stuff, best to read this in sequence.  If you jump in on the 4th part without having read the 3rd part, you are likely to get lost! Many more recaps to come.

Tuesday, July 19, 2011

Review of the Cell biology surrounding metal on metal hips (3 of x in a series)

Acta Orthop. 2008 Dec;79(6):734-47.
Metal-on-metal hip resurfacing arthroplasty: a review of periprosthetic biological reactions.
Mabilleau G, Kwon YM, Pandit H, Murray DW, Sabokbar A.

A third interesting finding.

This journal article reported that in skin tests done to detect osteolysis (a process in the bone joints that can lead to implant loosening or bone breakage, which in turn cause serious medical problems/often times associated with the metal debris from the implants), a higher rate of hypersensitivity reactions to cobalt and chromium were observed with cobalt chloride skin testing compared to the control group that had no osteolysis indicating a delayed hypersensitivity reaction. (Park et al, Jrnl of bone and joint surgery 2005.)  The findings suggested that early osteolysis is associated with abnormalities consistent with delayed-type hypersensitivity to metal.

The histological examination showed accumulation of  T-lymphocytes.

[I found this tidbit of interest because, for the most part, the physicians do not recommend skin testing to determine hypersensitivity to the metals.  I just asked my surgeon about this a week ago and was told that skin testing is not a reliable indicator of metal sensitivities.  Hmmm?  Perhaps his responce was based on skin testing prior to the surgery to indicate sensitivity to the metal not being a reliable indicator?]

Monday, July 18, 2011

Review of the Cell biology surrounding metal on metal hips (2 of x in a series)

Fascinating Review.

Acta Orthop. 2008 Dec;79(6):734-47.
Metal-on-metal hip resurfacing arthroplasty: a review of periprosthetic biological reactions.
Mabilleau G, Kwon YM, Pandit H, Murray DW, Sabokbar A.

first interesting point from this paper:
Unlike most organic chemicals, metal can not be eliminated from the tissues by metabolic degradation. [ I never knew before reading this why the kidney and liver were the key organs that might be affected]  Thus, they can only me eliminated from tissues by renal or gastronintestinal excretion.  There is evidence from a recent animal study to suggest that Chromium ions can accumulate in the liver.  Others have investigated potential long-term effects on the the kidney function resulting from Co and Cr wear in metal-on metal total hip replacements by measuring the serum metal ion levels and creatinine clearance  at 10- year follow -up in 75 patients conducted in 2007.

In this study, the serum creatinine clearance was normal indicating the kidney functioning is normal.

[comments by connie.  Just recently there was a much larger study conducted at Stanford and was published this year:

Nine-Year Incidence of Kidney Disease in Patients Who Have had Total Hip Arthroplasty. 

Chandran SE, Giori NJ. J Arthroplasty. 2011 Apr 18. [Epub ahead of print]
Department of Orthopedic Surgery, Stanford University, Stanford, California.

Abstract

Metal-metal total hip arthroplasty (THA) is contraindicated in patients with impaired renal function due to increased metal ion output relative to other bearings and renal excretion of metal ions. Although one can avoid a metal-metal THA in a patient with renal disease, a patient may be destined to develop renal disease later in life. In this study, we sought to determine the incidence of newly diagnosed renal disease in the 9 years after THA. Using the Department of Veterans Affairs national database, we identified 1709 patients who had a primary THA in 2000 without preexisting renal disease. We found the 9-year risk of developing chronic renal disease after primary THA to be 14% and severe or end-stage renal disease to be 6%
xxxx
What a difference 3 years make!  Very interesting indeed.
 

Sunday, July 17, 2011

Review of the Cell biology surrounding metal on metal hips (1 of x in a series)

This review  seems to be the most recent recap describing the biology of what happens in a cell when it comes into contact with the Chromium and Cobalt.  This topic is of interest because it provides the clues as to what the long term systemic bilogical consequences of the exposures to these particles might be.
 
Given the techncal nature of this subject, I will break this down into a series of commentaries on the content. I don't know how many posts will be required to cover this topic so will leave the series open ended (x.)
 
The following  abstract  will serve as the base document for comments. 
 
 I have gained some understanding of the link between the change in cell biology that is caused by these metal on metal hips and the possible assocation over time with cancer  from reading this document.  Understand, there have been no direct links showing cause and effect (metal from the hip causes cancer) but my sense from reading all of these documents is that it is not because there is no link but because there has not been enough data collected from the patients who have these hips in place over time to demonstrate unequivocally that there is a link.  The early studies in this arena whereby data has been collected over a 10 year period , have certainly demonstrated that over that time frame, the changes in the cell biology (DNA) which occur are those which are seen  in Lymphoma (cancer of the immune system) and Leukemia (Leukemia is cancer of the blood cells. It starts in the bone marrow, the soft tissue inside most bones.)  That doesn't mean one causes the other necessarily.  It means that there are similarities in the processes.
 
In prior articles, I have demonstrated that there is certainly enough seminal research in this field to strongly support the need for a concentrated effort in this area of research.  I believe that  the company's manufacturing the metal on metal hips should, in part, underwrite these studies as a part of the hip litigation settlement. 
 
As usual, I want to remind the readers that I am not a medical researcher nor do I have any training in this area of study.  I can only provide my own commentary into the questions.  I have no answers.
 
xx
 
Acta Orthop. 2008 Dec;79(6):734-47.

Metal-on-metal hip resurfacing arthroplasty: a review of periprosthetic biological reactions.

Source

Nuffield Department of Orthopaedic Surgery, Institute of Musculoskeletal Science, Botnar Research Centre, University of Oxford, Oxford, UK. guillaume.mabilleau@ndos.ox.ac.uk

Abstract

Metal-on-metal hip resurfacing arthroplasty has undergone a recent resurgence as an alternative treatment option for young and active patients with significant osteoarthritis. The claimed advantages of metal-on-metal hip resurfacing arthroplasty include lower wear rate, preservation of bone stock for subsequent revision procedures, restoration of anatomic hip mechanics, and enhanced stability due to the larger diameter of articulation. A disadvantage, however, is that the metal-on-metal resurfacing releases large amounts of very small wear particles and metal ions. The long-term biological consequences of the exposure to these Co-Cr particles and ions remain largely unknown. The purpose of this review is to provide an overview of the current literature on the adverse periprosthetic biological reactions associated with metal-on-metal hip resurfacing arthroplasty.

Friday, July 15, 2011

FDA's Role and Activities In the Metal-on Metal hips to assess safety and efficacy

 

FDA is actively working in several areas to further assess the safety and effectiveness of metal-on-metal hip implants. Some activities include a comprehensive review of:

  • Risk-benefit profiles
  • Utilization trends
  • Patient selection criteria
  • Pre-operative patient counseling
  • Surgical technique
  • Follow-up
  • Revision rates associated with metal-on-metal hip systems in the United States

In addition:

  • As a part of our effort to better understand possible adverse events associated with metal debris from metal-on-metal hip systems, we continue to review published literature, Medical Device Reports (adverse event reports) submitted to the Agency, post-approval study reports and data from several orthopaedic device registries from within and outside the U.S.
  • We have requested and will be reviewing device retrieval analyses from the manufacturers of the hip systems distributed in the U.S. This will help us understand how and why certain metal-on-metal implants fail over time.
  • We are pursuing collaborations with multiple partners domestically and internationally to fully understand the postmarket performance of metal-on-metal hip systems and to document the occurrence of and signs and symptoms associated with specific adverse events.
  • These efforts allow us to continue to investigate the safety and effectiveness of metal-on-metal hip implants systems and provide additional information to the public as it becomes available.

Update:


The FDA is continuing to gather and review all available information about currently marketed metal-on-metal hip systems, including information related to adverse events that may be associated with increase levels of cobalt and chromium in the bloodstream. To that end, on May 6, 2011 the FDA issued orders for postmarket surveillance studies to manufacturers of metal-on-metal hip systems. The FDA sent 145 orders to 21 manufacturers. Manufacturers will be required to submit a research protocol to the FDA that addresses specific safety issues related to these devices. Data from the studies conducted will enable the agency to better understand these devices and their safety profiles.

Metal-on-metal hip systems were marketed in the U.S. prior to 1976 legislation that gave the agency premarket authority over medical devices. As “preamendment devices,” they were automatically designated as Class III (higher risk) devices but were regulated under the 510(k) premarket notification program. The agency is currently reviewing all safety and effectiveness data related to these “preamendment devices,” including metal-on-metal hip systems, in an effort to determine their proper risk classification and how these devices should be regulated in the future. A decision on the proper classification of metal-on-metal hip systems is forthcoming but is unrelated to the postmarket surveillance order

Thursday, July 14, 2011

The FDA Surveillance Program

As you all know, the FDA has directed the companies who are selling hip replacements to being collecting data on the issues associated with the hips.  More information is contained on earlier posts.  I found the following information interesting on  a post today from Dr. David Lipschitz who is a geriatrician.  Here are the excerpts from his post:

The FDA encourages every patient with a metal-on-metal implant to contact their orthopedic surgeon, and whether symptomatic or not, the patient should agree to participate in the surveillance program. Then as much information as possible can be obtained and everything can be done to assure patient safety and the best possible quality of life.

The FDA surveillance program will include an analysis of every adverse effect from all types of metal implants, the reason why revision surgery is needed, and the incidence of pain and difficulty walking in those patients who do not have revision surgery. The FDA also suggests measuring patients’ chromium and cobalt levels before receiving a metal-on-metal implant and at frequent intervals for the first eight years after the surgery.


[I had never seen the details of the monitoring program before.   This is a great step and every patient with a hip should agree to be a part of that surveillance program.  Ask your surgeon on your next visit if they are participating in that program.  If there are no reports of issues, the frequency of issues will never surface!]

Wednesday, July 13, 2011

Hip Joints Set Off new Rush To Court

Key points  from an article published in the Wall St Journal on July 8th.  Article by Johathan Rockoff and Dionne Searcey. (Sorry, I can't access the URL.)

1.  1000 lawsuits have been filed in federal and state courts accusing DePuy of knowing about problems with some of its metal on metal hip joints before Depuy stopped making them.

2.  Depuy has turned over 200,000 of 18 Million  internal documents it is expected to submit  in the federal litigation.

3.  Depuy has set aside approximately $570 million last year for product liability costs and an additional $280 million to cover surgeries and other medical care for patients with those joints.

4.  The estimate is that about 37,000 patients in the US and about 93,000 world wide have received the recalled device.

5.  The Depuy spokesperson said the company will cover the cost of all medical care associated with the device, including replacement surgery.

6.  Depuy has helped nearly 27,000 callers, many of those calls led to claims for reimbursement.

7.   Though the Depuy spokesperson said the recalled   joints contain chromium and cobalt, she said it wasn't clear the devices contributed to elevated levels of those metals in patient's blood or how many patients have this problem.  [added by connie, good grief, it is quite hard to believe at this point that Depuy would hold this position.]

8.  In May of this year, the FDA said particles from the metal on metal hip joints might wear off and make their way into a patient's blood.  The agency said  this could contribute to  heavy concentrations of chromium and cobalt in teh body but wasn't sure it would cause symptoms.  The FDA just ordered the J and J (Depuy's parent) and other joint makers of metal on metal to monitor the devises for possible health risk.  [obviously, someone hasn't been reading the medical literature!...possible problems...possible symptoms...possible cause and effect?  Hard to believe these positions are maintained in light of the evidence.]

9.  Most replacements are metal on plastic but these joints also can wear down and potentially leave plastic debris in the body...says the Chair of the Dept of Ortho at the Mayo Clinic in Florida.

10.  The outcome of the litigation may hinge on what did Depuy know about these hips and when did they know it. ( see an earlier post on this: http://www.mydepuyhiprecall.com/2011/05/what-did-depuy-know-and-when-did-they.html )

11.  The Plaintiff lawyers contend that officials from the Australian medical device registry first warned Depuy about high failure rates and complications from these Depuy hips in 2007.

12.  The Depuy spokesperson said they monitored a number of databases like  the one in Australia but it wasn't until the British registry published information on the failure rates that Depuy decided to recall the hips.

Monday, July 11, 2011

Should you use a federal or state court if you are filing a suit re the depuy hip litigation?

I published something 5 or 6 months ago re the pluses and minuses of filing in each venue. (http://www.mydepuyhiprecall.com/p/questions-you-might-ask-law-firm.html)  As you know, I phoned the law firms that constitute the panel for the multi district federal litigation and I was surprised to find that each law firm had a different tact.  Some were planning to file all of their cases through MDL.  Some were planning to file most of them through state court  and some firms were filing in one or the other depending on the case.

The case below (excerpts only) started out in state court and the case was sent to the federal court only to be sent back to the state court.  Clearly the law firm that printed this release was anti Federal court filing and thus characterized the federal MDL process as slow.  It was interesting in any event.

Overview

A victim with a recalled DePuy ASR hip implant wins a legal victory by keeping her case out of federal court. The Federal District Court for the Eastern District of Wisconsin has ruled in favor of Letitia Malkmus’ motion to return her case to Wisconsin state court. This means she will not be forced to participate in the Multi District Litigation's (MDL)

Attorneys for DePuy Orthopaedics, Inc., the maker of the defective hip implants, argued that this case belonged in the MDL. The Federal Court disagreed with DePuy, siding with Mrs. Malkmus, and returned the case to Wisconsin State Court

The case is Letitia and Glen Malkmus v. DePuy Orthopaedics, Inc. and TRP & Associates, LLC, United States District Court for the Eastern District of Wisconsin, Case Number 2:11-cv-365.

Gee, I thought that when your attorney chose the venue, the case is handled in that venue.  Interesting that the court can send the case wherever it deems that it best be handled!

Mayo Clinic studies the squeaky-ceramic hip problem

With the growing success of joint replacement surgeries, patients have become accustomed to certain indignities related to having a metal replacement part in a hip, knee or shoulder. For example, they tend to set off airport metal detectors and attract attention of security personnel. Now, theres more. The Mayo Clinic Biomechanics Laboratory report released at the annual meeting of the American Academy of Orthopedic Surgeons sheds light on the potential causes of the squeak, thus guiding means of eliminating it.

The sound is associated with implants made of a material known as alumina ceramic-on-ceramic — and is audible to the person with the implant and those nearby. After 11000 cycles of tests in a mechanical simulator that reproduced the flexion and extension motions of the hip, Mayo Clinic investigators concluded that: • Squeaking occurred when the film fluid between the two moving surfaces was disrupted. • Disruption could be caused by the presence of particles that originate from wear and tear, or from imperfect alignment or positioning of implant surfaces. • Squeaking occured especially quickly under highest pressure on the artificial joint. • Once squeaking started, it didnt stop — and was constant at all frequencies tested. According to Robert Trousdale, MD, the lead Mayo investigator: Adding a small amount of lubricant solved the problem in the lab. Our research is helpful because it can be applied to devising a solution to the squeak problem.

Nice quick 2 minute video where the researcher discusses what they found with this.  I found this interesting because ceramic and ceramic is one option to consider in a revision surgery.

http://video.ezinemark.com/mayo-clinic-studies-squeaky-hip-implants-486043ff09c.html

Saturday, July 9, 2011

The association between metal ions from hip resurfacing and reduced T-cell counts

J Bone Joint Surg Br. 2006 Apr;88(4):449-54.

Hart AJ, Hester T, Sinclair K, Powell JJ, Goodship AE, Pele L, Fersht NL, Skinner J.

Source

Royal National Orthopaedic Hospital, Stanmore, UK. alisterjhart@yahoo.com

Abstract

We have studied the relationship between metal ion levels and lymphocyte counts in patients with metal-on-metal hip resurfacings. Peripheral blood samples were analysed for lymphocyte subtypes and whole blood cobalt and chromium ion levels in 68 patients (34 with metal-on-metal hip resurfacings and 34 with standard metal-on-polyethylene total hip replacements). All hip components were radiologically well-fixed and the patients were asymptomatic. Cobalt and chromium levels were significantly elevated in the patients with metal-on-metal hip resurfacings, compared with the patients with standard metal-on-polyethylene designs (p < 0.0001). There was a statistically significant decrease in the level of CD8(+) cells (T-cytotoxic/suppressor) (p = 0.005) in the metal-on-metal hip resurfacing group. A threshold level of blood cobalt and chromium ions was associated with reduced CD8(+) T-cell counts. We have no evidence that our patients suffered as a result of this reduced level of CD8(+) T-cells

[Added by Connie:  I published this study because it was a recent one that showed that there is a statistically significant decrease in the level of T cells in the metal on metal hip resurfacing group.

T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity.

Cellular immunity protects the body by:
  1. activating antigen-specific cytotoxic T-lymphocytes that are able to induce apoptosis in body cells displaying epitopes of foreign antigen on their surface, such as virus-infected cells, cells with intracellular bacteria, and cancer cells displaying tumor antigens;
  2. activating macrophages and natural killer cells, enabling them to destroy pathogens; and
  3. stimulating cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive immune responses and innate immune responses.

White blood cells fight infection. The white blood count (WBC) is part of a complete blood count (CBC) that is used to check your blood counts. There are several types of white blood cells. A differential test will show more detail about your white blood cell count:

Normal Adult Values
White Blood Cell Total4-11 k/ul
Lymphocytes22-44%
Monocytes0-7%
Granulocytes
Neutrophils40-70%
Eosinophils0-4%
Basophils0-1%
Note: Normal values will vary from laboratory to laboratory.

When you have a low white blood cell count there is an increased risk of infection. The level of risk depends on several factors:
  • How low your white blood count falls
  • How long your white blood count is low
  • Which type of low white blood cell count you have

Cancer /ˈkænsər/ ( listen) (medical term: malignant neoplasm) is a class of diseases in which a group of cells display uncontrolled growth, invasion that intrudes upon and destroys adjacent tissues, and sometimes metastasis, or spreading to other locations in the body via lymph or blood.
Researchers divide the causes of cancer into two groups: those with an environmental cause and those with a hereditary genetic cause. Cancer is primarily an environmental disease, though genetics influence the risk of some cancers.[1] Common environmental factors leading to cancer include: tobacco, diet and obesity, infections, radiation, lack of physical activity, and environmental pollutants.[1] These environmental factors cause or enhance abnormalities in the genetic material of cells.[2] Cell reproduction is an extremely complex process that is normally tightly regulated by several classes of genes, including oncogenes and tumor suppressor genes.

So, if your T cell counts are low due to the metal on metal hip implant, then it becomes difficult to fight off infection.  Infection is one of the causes of cancer....Make sense?]

Friday, July 8, 2011

Where do all of these medical articles come from?

Hi fellow bloggers and hip patients,

Some of my friends who read this blog have asked where these articles come from, especially the medical articles.  No, I don't publish just any old journal article.  This is the process I use:

1.  I choose a subject. As you all know, my current topic of interest is systemic long term effects of metal on metal implants on the organs.

2.  I have two primary sources of research:
  • PubMed is a free database accessing primarily the MEDLINE database of references and abstracts on life sciences and biomedical topics. The United States National Library of Medicine (NLM) at the National Institutes of Health maintains the database as part of the Entrez information retrieval system. PubMed was first released in January 1996.[1  As of 1 July 2011 (2011 -07-01)[update], PubMed has over 21.0 million records going back to 1966, selectively to the year 1865, and very selectively to 1809; about 500,000 new records are added each year. As of 1 July 2011 (2011 -07-01)[update], 11.9 million articles are listed with their abstracts and 3.3 million articles are available full-text for free.

  • Google Scholar is a freely accessible web search engine that indexes the full text of scholarly literature across an array of publishing formats and disciplines. Released in beta in November 2004, the Google Scholar index includes most peer-reviewed online journals of Europe and America's largest scholarly publishers
3.  I research the topic by subject matter or author and find the list of articles related to the subject.

4.  That subject matter is then expanded by doing a related link search or similarity search through Pub Med to see all of the available related  information on the topic.

5.  I often take the articles which I think are most informative and go into Google Scholar and feed in the documents from step 4 to see how frequently and recently the journal article is referenced.  That tells me something about the credibility of the research conducted as often, I am unfamiliar with the subject matter and researchers...or at least I was when I started doing this 8 months ago.

6.  the last step is to publish it on the site.

Most of what I publish contains my commentary. The publication is based on items I need to know for the future of my own health and hope that it will be of interest to others. 

 I try my best not to publish inflammatory documents that have no basis  in fact.  If someone sends me a published document  that says: "50% of the people who have metal on metal implants will require revision surgery", I would not publish that.  There is no basis to that claim.  It is what I would call inflammatory.

I do publish things that are investigatory pieces which may or may not result in a definitive conclusion but are very   important questions from a research perspective.

I have been questioned about the cancer journal articles...."aren't they inflammatory?"  I don't think so because I raise that issue/questions in an investigative sense.

I question everything. 

Connie

Wednesday, July 6, 2011

Quantification of t(14;18) in the lymphocytes of healthy adult humans as a possible biomarker for environmental exposures to carcinogens.

Source

Abstract

A t(14;18) chromosomal translocation is found in approximately 85% of follicular lymphomas by both cytogenetic and molecular analyses. This rearrangement deregulates expression of the bcl-2 proto-oncogene by translocation into the immuno-globulin heavy chain locus and is probably mediated by illegitimate V(D)J recombination. We have developed a quantitative nested PCR method for detecting this event in lymphocytes of healthy individuals. Genomic DNA is purified from peripheral blood lymphocytes, and 2.5 microg (representing 4 X 10(5) cells) are amplified with translocation-specific primers under conditions in which a single copy, if present, will give a detectable PCR product. Multiple replicates are analyzed for each individual, and Poisson statistics are then used to estimate the translocation mutant frequency. We have examined lymphocyte DNA from 34 healthy individuals by this assay and found the frequency of cells with t(14;18) to range from <0.8-96X10(-7). The molecular nature of the translocations has been investigated by determining the DNA sequence at the translocation junctions. In several individuals, multiple isolates of the same translocation event were recovered, indicating that the cell with the original translocation had undergone clonal expansion. In addition, multiple independent translocations were shown to occur within an individual. Since this translocation appears to be one step in the progression of a normal cell to a cancer cell, this assay may have utility as an effects biomarker for environmental carcinogen exposure.

[comments by connie:  So, here is a test that can detect possible cancers from blood lymphocytes-T (14;18) which was discussed by the committee on mutagencity/genotoxicty.  This will go on my to do list to discuss with my surgeon.  The question is, if there is concern regarding the possible association of metal induced cancers with total hip replacement (THA) that suggest that there is an increased risk of lymphoma and leukemia in patients with THA (reference was the jenkins article I published a few days ago) , how do you test for that?   While none of us likely understand the terminology in the above abstract, this is a test that I would like to have a  look at.  I  have been looking for some more recent methodologies but have found none....yet.
The other thing I find interesting about this is, my prior understanding was that "environmental" cancer data/testing is not readily portable to understanding hip stuff.  Well, I think we need to question that.  If there is a way to measure these chromosome translocations that are purportedly associated with metal induced cancers, then why would we not want to test this?
(In genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer.)]