Monday, October 31, 2011

Particulate debris from a titanium metal prosthesis induces genomic instability in primary human fibroblast cells.


I had not seen this article before.  I thought it was worth posting because a number of options are available for revisions which in fact contain Titanium!  Gee, I wonder what other metals have these issues which are being used in revisions?  Recall that chromosome aberrations are things that may in the long run, lead to potential cancer outcomes.  We just don't know. 

Br J Cancer. 2003 Feb 24;88(4):548-52.


Radiation and Environmental Science Centre, Dublin Institute of Technology, Ireland.


Previous studies detected both lethal and cumulative chromosomal aberrations in bone marrow and peripheral blood of patients with worn hip and knee replacements. This study shows that wear debris from a worn titanium metal on high-density polyethylene hip replacement also produces chromosomal instability and reproductive failure in cell culture. The progeny of these treated cells also displayed chromosomal instability, mainly consisting of chromatid breaks and minutes, and reproductive failure as determined by clonogenic survival many generations postexposure. These delayed effects are similar to those caused by the heavy metals cadmium and nickel and to those seen for low-dose radiation. These findings may have important implications with regard to the long-term risks of joint replacement surgery. This highlights the need for long-term epidemiological studies of patients with surgical implants

Sunday, October 30, 2011

Better alignment could cut need for hip replacements

By Dr. Lou Pack, Special to CNN  October 28th

Editor's note: Dr. Lou Pack practices in the Atlanta area, is a founding fellow of the American College of Rheumatology, a former clinical instructor of medicine at Emory University School of Medicine, a board-certified foot and ankle surgeon and the author of, "The Arthritis Revolution: Latest Research on Staying Active Without Pain Medication or Surgery," available on

(CNN) -- On October 4, Brian Williams continued his "NBC Nightly News" report on the "Largest Medical Device Failure Ever," involving "metal-on-metal" hip replacements manufactured by DePuy, a subsidiary of Johnson and Johnson.  (Click here to get to the Video: )

Originally reported in The New York Times on August 28, 2010, the story says 93,000 of these implants were recalled because of fracturing, dislocations, pseudotumors and metal particles flaking off and entering the bloodstream.

With all the recalls on our parts, you would think we were cars. And much like our motorized counterparts, this recall was not issued until more than two years after the Food and Drug Administration received complaints. Williams said that "so far this year, the FDA has received nearly 11,000 such complaints about metal-on-metal implants." By far, this is not the only recall. In July 2008, Zimmer Holdings issued a similar recall on its Durom Hip Cup, which had been used in 12,000 patients.

According to the National Center for Health Statistics, in 2004, there were more than half a million hip and knee replacements in the United States, and the numbers are growing. Researchers have predicted that if current trends continue, total knee replacements will increase 525% by 2030, and annual costs for knee and hip replacements will reach $62.5 billion by 2015.

Often, these prostheses don't last either, many needing replacement in 10 to 15 years. Although there are implants that have helped people regain active lives, obviously what we are doing is not working. Even though I was trained as a surgeon, I learned long ago and still believe that the best surgery is the one you can avoid.

So why are all these implants needed? By far, the largest numbers are utilized for those with osteoarthritis, the most prevalent form of arthritis, and now the No. 1 cause of pain and disability in the United States.

The National Institutes of Health, Arthritis Foundation, Centers for Disease Control and Prevention, and other reputable sources consistently list age, followed by weight, as the leading cause of osteoarthritis: Live long enough, and we will all get it. And despite the introduction of many new drugs and advanced surgical procedures, misunderstandings regarding the true cause of this disease have resulted in medicine's inability to prevent or stop it. This has led to an epidemic number of arthritic patients.

Indeed, some of what we have learned about osteoarthritis truly makes no sense, and one does not have to be a physician to come to that conclusion. It seems we are confused about the difference between a correlation and a cause.

We could say for example, that heart disease is also caused by age, since far more older people have it than do younger ones. Yet age is not a cause, but rather a correlation. In both heart disease and osteoarthritis, the pathological process actually begins in childhood, but it takes years before symptoms and tests can confirm the diagnosis.

In almost all cases of osteoarthritis, one knee or hip joint begins to hurt a patient first. Sometimes, that joint is the only one that ever shows symptoms. Certainly, one knee is not younger than the other. And in cases where both knees and hips are involved, the onset of one most always precedes the onset of the other and is more severe. If age is the primary cause of osteoarthritis, why do some 90-year-olds have no arthritis of their knees or hips, while some other far younger people have severe arthritic changes in these same joints, even in cases where there is no history of prior injury?

This logical fallacy is true of weight as well. As is the case in older people, many overweight people only have one knee or hip joint involved. Is all their weight on one side? Some significantly overweight people have no joint problems, whereas others, weighing far less, have arthritic joints. And why, if someone loses that excessive weight and has a joint replacement that is stronger than the original, does that same joint often have to be replaced again? There must be other causes.

Although many factors are involved, the average car's tires will wear out in about 40,000 miles. It can also be assumed that if you live to 80 or 90 years of age, some of your cartilage will also wear out. So age certainly is a factor. But you also know that you can drive just 10,000 miles in poor alignment and get far greater wear than you may have at 40,000 miles with properly aligned tires. That's exactly what happens to us: We get osteoarthritis of a particular weight-bearing joint because of improper alignment, which increases friction and pressure on a localized area of that joint, causing it to wear unevenly and prematurely.

Carry extra weight on that poorly aligned joint and yes, weight, too, is a factor. But make no mistake; it is the abnormal alignment that precipitates the process. And my work of 40 years shows that the correction of these misalignment issues has a very positive, often immediate effect on eliminating the symptoms of this disease, at times, even in very severe cases.

Medicine is traditionally very slow to change its thinking. Yet there is a wealth of credible data based on reliable studies to validate my premise that hips.

Sharma and colleagues published their findings in the prestigious Journal of the American Medical Association in 2001. They found that abnormal alignment of only 5 degrees from the ankle to the hip increased the progression of osteoarthritis three to four times and concluded that osteoarthritis was therefore a result of local mechanical factors. In 2008, researchers at the famed Mayo Clinic confirmed the results of this and a number of other previous studies and found that there was a 55% increase in the risks of arthritis of the knee for each degree of bad alignment from the ankle to the hip and stated that "age was only weakly associated with an increase risk."

You may have heard stupidity defined as "doing the same thing over and over and expecting a different result." We must begin to realize that the very same laws of physics apply to us as they do to all other things in the universe. The accepted science of biomechanics, i.e., the application of physical laws to human motion, is based on this and is something that must always be considered in those with osteoarthritis of their weight-bearing joints.

Abnormal alignment, such as a longer leg or flattened foot, primarily aligned by optimizing the position of our feet, the foundation of our entire skeletal system, is the root cause of osteoarthritis, and until we accept this, we cannot prevent or stop this disease. It is high time we focus on this, instead of continually trying to produce a better run-flat tire.

[ Connie's comments:  The idea that alignment might be the primary cause of these hip and knee problems is a really interesting proposition which  I had not heard before.    I wonder if the old adage is correct:  If you seek advise from  a surgeon, "the problem" will always be solved by cutting.  If you seek advise from an internist, they will investigate non surgical solutions first.  Just a thought.]

Friday, October 28, 2011

Federal Judge Schedules DePuy ASR Status Conference For November

New York, New York (PRWEB) October 27, 2011

Bernstein Liebhard LLP reports that on October 26, 2011, the Honorable David A. Katz, who is overseeing In re DePuy Orthopaedics, Inc. Hip Implant Liability Litigation (“MDL No. 2197”), issued an order scheduling a status conference with a committee of lawyers appointed by the court to help coordinate the litigation. The status conference is set for November 22, 2011, at 11:00 a.m. at the James M. Ashley and Thomas W.L. Ashley Courthouse in Toledo, Ohio. Subsequently, an open court conference will commence at 1:00 p.m. that same day

Discovery Updates In DePuy ASR Litigation Since Last Status Conference
The last status conference in the DePuy ASR MDL was held on July 26, 2011 in San Francisco, California.  Although the DePuy ASR MDL is currently underway in the U.S. District Court for the Northern District of Ohio, the July status conference was held in California state court before the Honorable Richard A. Kramer, who is overseeing the consolidated California state court DePuy ASR litigation. The purpose of holding a joint status conference was to promote federal and state coordination of the DePuy ASR litigation. Since that time, a series of orders have been issued and depositions have been noticed in the federal DePuy hip replacement lawsuits. Most notably, Judge Katz issued several Case Management Orders, requiring plaintiffs’ counsel to submit a Plaintiff Fact Sheet and Medical Records Authorization on behalf of their clients who have undergone revision surgery or are scheduled to undergo revision surgery.  In a mass tort case, such as the DePuy ASR MDL, Plaintiff Fact Sheets are discovery tools used by defendants to obtain basic information about the plaintiff as well as specific information about the nature of plaintiff’s injuries. Plaintiffs must also produce documents that support their claims against defendants.  

Thursday, October 27, 2011

Study Evaluates Industry Payments To Orthopedic Surgeons

From Red Orbit.
An analysis of financial payments made by orthopedic device manufacturers to orthopedic surgeons shows that the patterns of payments from 2007 to 2010 appear to be complex with a reduction in the total number of payments and the total amount of funds distributed after payment disclosure was required, as well as an increase in the proportion of consultants with academic affiliations, according to a report in the October 24 issue of Archives of Internal Medicine, one of the JAMA/Archives journals. The article is part of the journal’s Health Care Reform series.

“There is ongoing discussion of physician relationships with the pharmaceutical industry and medical device manufacturers,” the authors write as background information in the article. “Our objective was to use data made available by a U.S. Department of Justice (DOJ) lawsuit to describe the extent of orthopedic surgeons’ financial relationships with implant manufacturers.” In 2005, the DOJ launched an investigation into payments made to orthopedic surgeons by the five largest makers of artificial hips and knees and reached a settlement with the companies in 2007.

Jason M. Hockenberry, Ph.D. then of The University of Iowa and Iowa City Veterans Affairs Medical System, Iowa City, now with Rollins School of Public Health, Emory University, Atlanta, and colleagues used data made available by the 2007 Department of Justice settlement with five major device implant manufacturers to examine financial payments made by orthopedic device makers to orthopedic surgeons. The authors examined the number of surgeons receiving payments, the amount of money paid and the types of payments made in the year prior to (2007), the year immediately following the DOJ settlement (2008), and the subsequent years (2009-2010), during which three companies continued to voluntarily report data.

In 2007, the five orthopedic device makers made 1,041 payments to 939 orthopedic surgeons totaling more than $198 million. In 2008, the year immediately following the settlement with the DOJ, the manufacturers made 568 payments to 526 orthopedic surgeons totaling more than $228 million; however, the authors note that this figure includes $109 million in royalty buyouts from one company.
When limiting analysis to only the three companies that reported data for all four years, the authors found that mean (average) payment made by device makers per surgeon was $212,740 in 2007, $193,943 in 2008, $246,867 in 2009 and $233,108 in 2010.

Additionally, the proportion of surgeons receiving payments who had academic affiliations increased from 39.4 percent in 2007 to 44.9 percent in 2008. The authors observed similar patterns in 2009 and 2010 for the three companies that continued disclosing payments by choice.

“Although mandating disclosure of consulting payments and efforts by academic institutions to ‘monitor their own’ seem prudent, universal and detailed disclosure with standardized reporting formats and data elements would make these data more useful to patients, providers and policymakers,” the authors conclude. “There is a need for clearer specific requirements for disclosure to allow for meaningful long-term analyses to be performed.”

(Arch Intern Med. 2011;171[19]:1759-1765. Available pre-embargo to the media at

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Invited Commentary: Industry Payments to Physicians
In an invited commentary, Robert Steinbrook, M.D., of Yale School of Medicine, New Haven, Conn., analyzed the findings of Hockenberry et al saying they “show a complex pattern, with substantial variation between the five manufacturers.”

“According to the study, the approximately 1,000 physicians who received payments in 2007 represent only about 4 percent of the orthopedic surgeons in the United States,” notes Steinbrook. “Unfortunately, the public data provide no information about how the payments relate to research and device development, the choice of hip or knee implant or other aspects of patient care.”

“The disclosure of industry payments should not divert attention from the real issues with regard to conflict of interest,” writes Steinbrook. “These are the minimization or elimination of financial ties between physicians and industry in areas other than research support, bona fide consulting related to basic and clinical research, and legitimate payments related to intellectual property. Although many well-publicized examples with regard to conflict of interest involve physicians in specific fields, such as orthopedics or psychiatry, the issues are similar for all specialties.”

“In the United States, the rules regarding the disclosure of industry payments are about to change,” Steinbrook notes. “With mandatory disclosure of payments and amounts imminent, there should be many new opportunities to better control conflicts of interest in medicine.”

(Arch Intern Med. 2011;171[19]:1765-1766. Available pre-embargo to the media at

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Wednesday, October 26, 2011

Is the FISH technology cost effective? (series 5 of 5)

I found this article for our series on metal on metal testing for carcinogens for hip patients (read 4  prior posts to come up to speed.)  This was published in 2008 so I am guessing that the technology has come a long way since then.  This abstract addresses the cost effectiveness of the testing.

Will try to get some calls made in the next few days to see how well this process fits the hip testing for potential carcinogens.

Lab Chip. 2008 Dec;8(12):2151-6. Epub 2008 Oct 23.
An integrated microfluidic chip for chromosome enumeration using fluorescence in situ hybridization.


Department of Electrical and Computer Engineering, 2nd Floor ECERF, University of Alberta, Edmonton, CanadaT6G 2V4.

Fluorescence in situ hybridization (FISH) is a powerful technique for probing the genetic content of individual cells at the chromosomal scale. Conventional FISH techniques provide a sensitive diagnostic tool for the detection of chromosomal alterations on a cell-by-cell basis; however, the cost-per-test in terms of reagent and highly qualified labour has prevented its wide-spread utilization in clinical settings. Here, we address the inefficient use of labour with the first integrated and automated on-chip FISH implementation, one that requires only minutes of setup time from the technician. Our microfluidic chip has lowered the reagent use by 20-fold, decreased the labour time by 10-fold, and substantially reduced the amount of support equipment needed. We believe this cost-effective platform will make sensitive FISH techniques more accessible for routine clinical usage.
Microfluidic chip that lowered the cost-per-test of FISH by 90%.

Recently, the first demonstration of Metaphase FISH on chip has led to renewed efforts towards automating the metaphase FISH protocol.[10] Metaphase FISH had continued to be difficult to integrate owing to the complex sample preparation protocol often spanning over 3 weeks. New reports confirm that a research group in Denmark have tested successfully a novel lab on chip device to integrate the entire sample preparation protocol for Metaphase FISH called FISHprep.

Tuesday, October 25, 2011

FISH and Depuy hip testing in the future for carcinogens? (series 4 of x)

[Please don't go out asking your orthopedic  surgeon to order these tests until we uncover the following:
  • Who can perform this test?
  • What does it cost?
  • How complicated is it?
  • What is the right population to run this test on in terms of length of implant in ones body (is it better to perform this test at 5 years, 2 years, 10 years?
  • How reliable is it?
  • What can we do if we have the results?  Is there some action that can be taken if the results are not good? ]

FISH (fluorescence in situ hybridization) is a cytogenetic technique developed by Christoph Lengauer that is used to detect and localize the presence or absence of specific DNA sequences on chromosomes. FISH uses fluorescent probes that bind to only those parts of the chromosome with which they show a high degree of sequence complementarity. Fluorescence microscopy can be used to find out where the fluorescent probe bound to the chromosomes. FISH is often used for finding specific features in DNA for use in genetic counselling, medicine, and species identification. FISH can also be used to detect and localize specific mRNAs within tissue samples. In this context, it can help define the spatial-temporal patterns of gene expression within cells and tissues.

In medicine, FISH can be used to form a diagnosis, to evaluate prognosis, or to evaluate remission of a disease, such as cancer. Treatment can then be specifically tailored. A traditional exam involving metaphase chromosome analysis is often unable to identify features that distinguish one disease from another, due to subtle chromosomal features; FISH can elucidate these differences. FISH can also be used to detect diseased cells more easily than standard Cytogenetic methods, which require dividing cells and requires labor and time-intensive manual preparation and analysis of the slides by a technologist. FISH, on the other hand, does not require living cells and can be quantified automatically, a computer counts the fluorescent dots present. However, a trained technologist is required to distinguish subtle differences in banding patterns on bent and twisted metaphase chromosomes.

Although interphase fluorescence in situ hybridization (FISH) is a sensitive diagnostic tool used for the detection of chromosomal abnormalities on cell-by-cell basis, the cost-per-test and the technical complexity of current FISH protocols has inhibited its widespread utilization. Lab-on-a-chip or microfluidic devices, incorporate networks of microchannels that can miniaturize, integrate and automate conventional analytical techniques onto chip-style platforms. Since microchannels permit sophisticated levels of fluid control (down to picolitres), these devices can reduce analysis times, lower reagent consumption, and minimize human intervention.

Currently, FISH has been performed on glass microfluidic platforms that standardize much of the protocol offering repeatable results that are accurate, cost-effective and easier to obtain in a clinical setting.

Compared to conventional FISH methods, these first implementations of on-chip FISH provide a 10-fold higher throughput and a 10-fold reduction in the cost of testing, enabling the simultaneous assessment of several chromosomal abnormalities or patients.[8] It is increasingly essential that diagnostic tests determine the type and extent of chromosomal abnormalities for more informed diagnosis and for appropriate choice of treatment strategies. Since the on-chip FISH technique is 10-20 times more cost-effective than conventional methods, and can be fully integrated and automated,[9] this technology will make widespread genetic testing of patients more accessible in a clinical setting.

[Tomorrow I will begin to  address the cost/complexity of the tests]

File:FISH (technique).gif

Monday, October 24, 2011

Evidence for a possible need for Cytogenic testing with Depuy hips or MoM hips (3 of x)

Previous work (below) has shown a significantly higher rate of chromosomal aberration in local bone-marrow cells adjacent to the prosthesis at revision surgery.

Study One

Clin Orthop Relat Res. 1996 Aug;(329 Suppl):S269-79.

Preliminary observations on possible premalignant changes in bone marrow adjacent to worn total hip arthroplasty implants.


Department of Histopathology, University of Bristol, United Kingdom.


Previous epidemiologic studies have suggested that there may be a risk of malignancy, especially lymphoma and leukemia, after joint replacement, but the followup has been relatively short. This is a preliminary study to see if there is any biologic basis for such a risk. Blood and bone marrow samples from 71 patients at revision arthroplasty of a loose or worn prosthesis and 30 control patients at primary arthroplasty were analyzed with cytogenetic techniques and molecular biology. There was a higher chromosomal aberration rate in cells adjacent to the prosthesis at revision surgery compared with iliac crest marrow from the same patients or with femoral bone marrow at primary arthroplasty. Clonal expansion of lymphocytes without a serum paraprotein was seen in 2 of 21 patients at revision arthroplasty performed more than 10 years after primary arthroplasty. The results of this preliminary study suggest that future epidemiologic studies should concentrate on patients with longer postoperative intervals to see if there is any risk that would be pertinent to a young patient at primary arthroplasty.

Study Two:

Jenkins L Standen, GR, Ellis L et al. 
 Detection of T (14;18) translocations in peripheral blood lymphocytes from patients with total hip atheroplasty. 
 J Bone Joint Surg [Br] 1999;81-B Supp 111. 319.
There is a concern regarding the possible association between metal induced cancers with total hip atheroplasty.  Some epidemiological studies suggest there is increased risk of leukemia and lymphoma in patients with replacements in situ after 10 years.  Wear debris including the potential  carcinogens from  chromium and nickle accumulate at the highest levels in the lymph nodes and bone marrow.  A cytogenic study has shown a significantly higher rate of chromosomal aberration in local bone-marrow cells adjacent to the prosthesis.

The preliminary data shows that there is a higher frequency of T (14-18) translocations in patients with revsion surgery.

Sunday, October 23, 2011

Cytogenetic analysis by chromosome painting. (a series 2 of x)


This is the second in a series on the chromosome painting which is a test that is used to determine  genetic damage.  See the prior post to understand why we are discussing this topic.
Essentially, there is a question about long term systemic effects  of chromosome aberrations in bone-marrow cells adjacent to the prosthesis at revision surgery.  This test is a means to identify those aberrations.  I will have more details on this in the coming weeks but it is my understanding that changes in these chromosomes may not be seen for 10-20 years.
I don't think there have been enough studies to substantiate much but there are two studies that have shown significantly higher rate of chromosomal aberration in local bone-marrow cells adjacent to the hip.
Cytometry. 1994 Mar 15;18(1):2-10.


Department of Pathology, University of Cambridge, United Kingdom.


Chromosome painting is a term used to describe the direct visualisation using in situ hybridisation of specific chromosomes in metaphase spreads and in interphase nuclei. Chromosome painting, coupled with fluorescence in situ hybridisation (FISH), is now used routinely to enhance the identification of chromosomal rearrangements, the assignment of breakpoints, and the determination of the origin of extra chromosomal material. Amplification of small numbers of flow-sorted chromosomes by the polymerase chain reaction allows labelled chromosome paints to be generated in a matter of days. These technologies have enabled the development of reverse chromosome painting, in which the paint is produced from sorted aberrant chromosomes and hybridised back onto normal metaphase spreads to identify directly the composition of the aberrant chromosome. Reverse chromosome painting is able to identify not only the chromosomal origin of marker chromosomes but also the regions and breakpoints involved. In some cases, such as interstitial translocations and complex marker chromosomes, the combination of conventional (forward) chromosome painting and reverse chromosome painting combine to provide a definitive analysis of the rearrangement. With the availability of chromosome paints and painting kits from a variety of commercial sources, multicolour chromosome painting has now become a routine method of analysis in the clinical cytogenetic laboratory.

Friday, October 21, 2011

What are Cytogenic labs and why might the Depuy hip patients have interest in these labs?

Well, I continue to pursue the identification of tests that will provide me with some feedback on the long term biologic effect of the is ware debris on my body.  There is a test that might be available to determine whether  there are measurable chromosome defects as a result of these hips.  Why care?  cancer potential. That's why.  Particulate wear debris accumulates in the tissue adjacent to the prosthesis and disseminates in the body to the liver, spleen, bone marrow and lymph nodes, with the highest levels being detected in the local bone marrow and lymph nodes.

A number of studies have shown a significantly higher rate of chromosomal aberration in local bone-marrow cells adjacent to the prosthesis at revision surgery compared with bone marrow from the iliac crest from the same patient or from a primary hip replacement.

So, my investigation will now begin into the chromosome painting method of fluorescent in situ hybridisation (FISH for short.)  This  is a well recognised and sensitive method for identifying genetic damage.

Just  a quick check of these labs show that the Mayo Clinic has one.  I will most definately check into this now as my surgery is in a few weeks and I would like to be able to get the samples required to run this test.

So, my orthopedic surgeon is very willing to support my testing and he and I have the same question about what I will do with the results.  My answer is to monitor the chromosome damage if there is any from a base line of 5 years.    Resulting damage does not seem to show up for 10 years or longer.

Will write a few more posts on this and then start my phone calling to see if one of these labs will run the baselines.

Wednesday, October 19, 2011

Will Johnson & Johnson Have to Answer to Congressional Committee for DePuy Metal-on-Metal Hips?

Yesterday House Democrats from the Energy and Commerce Committee, led by Representative Henry Waxman of California, urged Republicans to hold hearings to examine certain medical devices, more specifically metal-on-metal hip implants like the DePuy ASR and the DePuy Pinnacle, as well as brain stents, both of which have developed serious defects after being implanted in patients, and they cited underregulation as the cause. 

The House Democrats outlined that the metal-on-metal hip implants have tiny metal particles that wear and enter the bloodstream from the friction of the ball and the cup, per the U.S. Food and Drug Administration (FDA). The agency has received over 5,000 complaints in the first six months of 2011, which was more than the agency had received in the prior four years combined.

Kind of interesting that now the congress wants to advocate holding hearings on the Depuy hip recall.
Here is the orignal letter:  I suggest glancing through it.

This information came from  the Ennis and Ennis site.

Tuesday, October 18, 2011

Cutaneous and systemic hypersensitivity reactions to metallic implants

Dermatitis. 2011 Apr;22(2):65-79.


Basko-Plluska JL, Thyssen JP, Schalock PC.


Department of Medicine, Section of Dermatology, The University of Chicago, Chicago, IL, USA.


Cutaneous [skin] reactions to metal implants, orthopedic or otherwise, are well documented in the literature. The first case of a dermatitis reaction over a stainless steel fracture plate was described in 1966. Most skin reactions are eczematous and allergic in nature, although urticarial, bullous, and vasculitic eruptions may occur. Also, more complex immune reactions may develop around the implants, resulting in pain, inflammation, and loosening. Nickel, cobalt, and chromium are the three most common metals that elicit both cutaneous and extracutaneous allergic reactions from chronic internal exposure. However, other metal ions as well as bone cement components can cause such hypersensitivity reactions. To complicate things, patients may also develop delayed-type hypersensitivity reactions to metals (ie, in-stent restenosis, prosthesis loosening, inflammation, pain, or allergic contact dermatitis) following the insertion of intravascular stents, dental implants, cardiac pacemakers, or implanted gynecologic devices. Despite repeated attempts by researchers and clinicians to further understand this difficult area of medicine, the association between metal sensitivity and cutaneous allergic reactions remains to be fully understood. This review provides an update of the current knowledge in this field and should be valuable to health care providers who manage patients with conditions related to this field.

[From Connie : Interesting that the 2 of the 3 most common metals that elicit reactions from chronic internal exposure are Chromium and Cobalt.  Unfortunate that we just don't know what the long term systemic "reactions" are at this point.]

Monday, October 17, 2011

Effects of Cobalt Nanoparticles on Human T Cells In Vitro.

[  Connie's preamble:  I have  spent a number of months looking at the potential genotoxic effects of Chromium on cells in patients with hip implants.  I just noted this article which talks about the potential gentoxic/cytotoxic effects that Cobalt might have  on the patients T cells. This article was released pre publication in the journal.
In genetics, genotoxicity describes a deleterious action on a cell's genetic material affecting its integrity
Cytotoxicity is the quality of being toxic to cells.
 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. Lymphocytes identify invaders in the body and destroy them.  In this case, we would be targeting Cobalt as an invader in the body which the system would want to wipe out.  If the T lymphocytes are not working properly and are inhibited, problems could arise of various sorts. 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.
These tests were conduced in vitro. that is, they are lab experiments NOT conducted on humans or organisms.]
Biol Trace Elem Res. 2011 Oct 4. [Epub ahead of print]


Department of Orthopedics, The First Affiliated Hospital of Soochow University, Shizi Street, Suzhou, 215006, Jiangsu Province, People's Republic of China.


Limited information is available on the potential risk of degradation products of metal-on-metal bearings in joint arthroplasty. The aim of this study was to investigate the cytotoxicity and genotoxicity of orthopedic-related cobalt nanoparticles on human T cells in vitro. T cells were collected using magnetic CD3 microbeads and exposed to different concentrations of cobalt nanoparticles and cobalt chloride. Cytotoxicity was evaluated by methyl thiazolyl tetrazolium and lactate dehydrogenase release assay. Cobalt nanoparticles dissolution in culture medium was determined by inductively coupled plasma-mass spectrometry. To study the probable mechanism of cobalt nanoparticles effects on T cells, superoxide dismutase, catalase, and glutathione peroxidase level was measured. Cobalt nanoparticles and cobalt ions could inhibit cell viability and enhance lactate dehydrogenase release in a concentration- and time-dependent manner (P < 0.05). The levels of cobalt ion released from cobalt nanoparticles in the culture medium were less than 40% and increased with cobalt nanoparticles concentration. Cobalt nanoparticles could induce primary DNA damage in a concentration-dependent manner, and the DNA damage caused by cobalt nanoparticles was heavier than that caused by cobalt ions. Cobalt nanoparticles exposure could significantly decrease superoxide dismutase, catalase, and glutathione peroxidase activities at subtoxic concentrations (6 μM, <CC(50)). These findings suggested that cobalt nanoparticles could generate potential risks to the T cells of patients suffer from metal-on-metal total hip arthroplasty, and the inhibition of antioxidant capacity may play important role in cobalt nanoparticles effects on T cells

Sunday, October 16, 2011

Sensitivity and specificity of blood cobalt and chromium metal ions for predicting failure of metal-on-metal hip replacement.

Interesting study.  This is the first one I have seen that examines the predictive nature of blood ion levels for diagnosing hip failure.  They seemed to find the optimal cut off level for the Cr Co blood tests were about 5ppb or 5 mcg/l.   (Likely that you have received your metal tests in micrograms per liter which is I believe the same as parts per billion (PPB )]

Thier conclusion was that Blood metal ions had good discriminant ability to separate failed from well-functioning hip replacements.

So If I look at my test results, they are way over the cut off:

Chromium Blood ion test taken on 1/4/11
Cobalt blood ion test taken on 1/4/11
24 hour Urine chromium test taken on 1/30/11
Other Urine chromium test taken on 1/30/11
Cobalt Urine test taken on 1/30/11
2nd blood chromium test taken on 2/9
2nd blood cobalt test taken on 2/9
Actual result
34 mcg/l
> 10.0 ug/l
21.6 ug/l
29.5 ug/l
Reported normal level
.5 ug/l
Multiple over normal
5-100 x

J Bone Joint Surg Br. 2011 Oct;93(10):1308-13.


Imperial College London, Department of Musculoskeletal Surgery, Charing Cross Hospital Campus, Fulham Palace Road, London W6 8RF, UK.


Blood metal ions have been widely used to investigate metal-on-metal hip replacements, but their ability to discriminate between well-functioning and failed hips is not known. The Medicines and Healthcare products Regulatory Agency (MHRA) has suggested a cut-off level of 7 parts per billion (ppb). We performed a pair-matched, case-control study to investigate the sensitivity and specificity of blood metal ion levels for diagnosing failure in 176 patients with a unilateral metal-on-metal hip replacement. We recruited 88 cases with a pre-revision, unexplained failed hip and an equal number of matching controls with a well-functioning hip. We investigated the 7 ppb cut-off level for the maximum of cobalt or chromium and determined optimal mathematical cut-off levels from receiver-operating characteristic curves. The 7 ppb cut-off level for the maximum of cobalt or chromium had a specificity of 89% and sensitivity 52% for detecting a pre-operative unexplained failed metal on metal hip replacement. The optimal cut-off level for the maximum of cobalt or chromium was 4.97 ppb and had sensitivity 63% and specificity 86%. Blood metal ions had good discriminant ability to separate failed from well-functioning hip replacements. The MHRA cut-off level of 7 ppb provides a specific test but has poor sensitivity.

Friday, October 14, 2011

Former gymnast sues over hip op

Bath Chronicle, England  October 13th, 2011

A former gymnast who was a "poster lady" for a hip resurfacing implant is taking legal action against its manufacturer after it left her in severe pain.

Penny Brown, who lives near Bath, is joining a group action by more than 300 UK patients against DePuy – part of Johnson & Johnson – after doctors said she would need further surgery because the implant had worn prematurely.
The Articular Surface Replacement (ASR) treatment was available to patients on the NHS and globally but was withdrawn last year in a worldwide recall.

Ms Brown, 51, agreed to advertise ASR after undergoing an operation in 2004 to relieve her from constant pain caused by osteoarthritis.

"I was advised to have the ASR resurfacing procedure rather than a total hip replacement on the basis that it would last much longer, be safer and reduce the likelihood of further surgery during my lifetime," she said.

Initially, ASR transformed her life, so much so that she agreed to become the face of the treatment for DePuy.

She said: "I was included in all the promotional literature and went on stage to give a live interview on my personal story as a patient and how the ASR had transformed my life.

"I was DePuy's patient brand and my image was used extensively around the world over a four-year period between 2004 and 2008. I even counselled patients about having ASR components implanted."
During 2009 Ms Brown started to experience groin pain, and by March this year could feel a clunking sensation when walking. The pain gradually got worse and she was eventually told in May that she would need corrective surgery as a result of the premature wearing of the ASR component.

Ms Brown said: "I couldn't believe it. It seemed so ironic that having promoted the product I was now a victim of the ASR. I have been living with constant discomfort, I can't sit or stand for long periods and my personal and professional life suffered greatly.

"I was a successful businesswoman at the top of my profession and never had any significant periods of time off work due to illness."

She said that since her revision operation last month she had been bed-bound and unable to work.
"My life has been devastated and I not only feel let down personally but also feel guilty that I might have encouraged others to have the ASR implanted."

Ms Brown, who has an 18-year-old daughter at university and lives with her 48-year-old long-term partner, is being supported by law firm Leigh Day & Co.

It is leading the case against the manufacturer and says the recall should have occurred far sooner.
A spokeswoman for DePuy said: "Our top priority is to provide Ms Brown and all ASR patients with the information and support they need. DePuy is committed to addressing reasonable and customary costs of testing and treatment for reasons related to the recall, including revision surgery if necessary, for Ms Brown and other ASR patients."

Thursday, October 13, 2011

The DePuy ASR Recall On CBS Atlanta News

The video of a news story by Stephany Fischer of CBS Atlanta News is shown here:

DePuy declined an interview with after their request but did make the following statement:

DePuy’s top priority is and always has been patient safety. In August 2010, DePuy issued a voluntary recall of the ASR Hip System after receiving new information from the UK National Joint Registry as part of the company’s ongoing surveillance of post-market data concerning the ASR Hip System. After reviewing this data, DePuy decided it was in the best interests of patients to voluntarily recall the ASR Hip System. This data showed a five-year revision rate of approximately 12 percent for the ASR Hip Resurfacing System and approximately 13 percent for the ASR XL Acetabular System, which was not in line with previously reported data.

DePuy’s previous analyses of collective post-market data from a variety of sources — including national joint registries, published literature, company-sponsored clinical trials, internal complaints data and external clinical research reports — had shown lower revision rates.
We understand that this recall is concerning for patients, their family members and surgeons. Since the recall decision was made, DePuy has worked to provide patients and surgeons with the information and support they need.

DePuy is committed to addressing reasonable and customary costs of testing and treatment for reasons related to the recall, including revision surgery if necessary. DePuy will also pay for reasonable expenses related to receiving care, such as lost wages and travel costs. …”

Wednesday, October 12, 2011

DePuy Pinnacle Hip Replacement MDL Lawsuits

Posted On: October 7, 2011 by Dr. Shezad Malik   

More than 500 lawsuits have been filed in Northern District of Texas federal court over DePuy Pinnacle hip replacements problems. The plaintiffs have alleged that DePuy hips, caused individuals to experience severe pain and early failure of their artificial hip implant.

In May 2011, the U.S. Judicial Panel on Multidistrict Litigation, JPML, ordered that every DePuy Pinnacle hip lawsuit filed in any U.S. District Court throughout the country be transferred to the Northern District of Texas as part of a multidistrict litigation, or MDL.

According to court documents released October 6, there are now at least 538 complaints consolidated before U.S. District Judge James E. Kinkeade in the DePuy Pinnacle MDL. As DePuy Pinnacle hip replacement lawyers continue to evaluate, investigate and file new cases in federal court, the number of lawsuits is expected to continue to grow. Many medical experts anticipate that thousands of people who are impacted by the alleged defective medical product, will ultimately file a complaint.

This scenario is currently being played out in the Northern District of Ohio federal court system, where another metal on metal DePuy hip product has been consolidated for litigation purposes. In August 2010, DePuy recalled its flagship artificial metal on metal hip product, the DePuy ASR.

watch this abc news video

All of the suits involve similar allegations that the DePuy Pinnacle Acetabular Cup System was defectively designed or manufactured, and that inadequate warnings were provided about the risk of early complications or problems, which have been developing within a few years of the surgery. In many cases, the DePuy Pinnacle hip replacement complications result in the need for additional surgery to replace or revise the hip replacement.

Many of the complaints allege that DePuy, a subsidiary of Johnson & Johnson, has been aware of the problems with their metal-on-metal hip implants for some time and that a DePuy Pinnacle hip recall should have been issued several years ago.

As described above, Johnson & Johnson and DePuy also face thousands of lawsuits over the recalled DePuy ASR hip replacement. The DePuy ASR hip was approved as a substantial equivalent design to the DePuy Pinnacle metal-on-metal hip, and the allegations raised regarding design problems with the two devices are similar.

Over the past year, concerns about all metal-on-metal hip replacements have been growing. Last October, the American Academy of Orthopaedic Surgeons (AAOS) issued a warning about potential problems with metal on-metal hip replacements, indicating that patients and the medical community should be aware that pain months after hip replacement surgery may be a sign of metal-on-metal hip cobalt toxicity.

Earlier this year, the FDA launched a new website to provide information about the risks associated with metal-on-metal hip replacements.

Tuesday, October 11, 2011

Review of the Implications of MOM hips to cancer addressing the creation of abnormal chromosomes (genotoxic effects-2 posts back-), Immune Mediated responses (last post) and oxidation of Cr 3 to 6 and visa versa-below-. (3 of 3)

Oxidative Damage / exerpts from  Acta Orthopaedica 2008 79 (6) 734-747 University of Oxford
//Metal-induced intracellular effects

1.  Reactions with metal ions can lead to generation of free radicals:  reactive oxygen species (ROS) and reactive nitrogen species (RNS) which in , cause cellular dysfunction. 

2.  Inside the cells, Cr 6 is oxidized to Cr 3 in a series of steps that generate free radicals.

3.  Free radicals catalyze the oxidation of protein and phospholipids.

4.  That process leads to the formation of malondialdeyde which can react with DNA bases to form DNA protein cross links

5.  Permanet modification of genetic material resulting from this oxidative damage represents the first step in mutagenesis and carcinogenesis.

6.  Direct binding of Cr 3 to DNA is well documented.

7.  In cells , two main processes exist to correct DAN aberrations to restore the integrity of the genome.

8.  Under stimulation by Cobalt 2 and Chromium 6, both of these mechanisms are inhibited.

9.  Landon (2004) investigated changes in metal ion levels and chromosome aberrations in patients within two years of receiving metal on metal atheroplasties.

10  The authors noted an increase in chromosome translocations and aneuploidy in peripheral blood lymphocytes at 6, 12, 24 months after surgery.

  • Aneuploidy is an abnormal number of chromosomes, and is a type of chromosome abnormality. Some cancer cells have abnormal numbers of chromosomes.[1] Aneuploidy occurs during cell division when the chromosomes do not separate properly between the two cells...The question is what is the relationship between the metal on metal hip and long term systemic effects with things like cancer?

  • 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.

11.  The authors noted the changes were progressive.

12.  The authors didn't find any statistically significant correlations over those short time frames between chromosomal translocations and Co and Cr concentrations in the whole blood.

following are some summary steps of this oxidation process.  A bit technical but helpful:

  • Different pathways are  used by metal ions to enter the cells
  • Chromium 6 can cross the cell membrane
  • Chromium 6 undergoes rapid metabolic reduction to form Chromium 5, chromium 4 and then chromium 3.
  • At each step of the Cr  6 reduction, ROS and RNS are generated (see above for definition of these terms)
  • Cr 3 can cross the cell membrane and participate in alteration of DNA.
So my question remains, did we start with Chromium 6 which was oxidized to Chromium 3 in our body?  Yes or No?  If yes, and the oxidation process is a known cause of DNA damage and is the first step in carcinogenesis and mutagenesis, is this not a problem?

I think I have to call these authors from Oxford to get an answer to this question.  The general orthopedic surgeons do not know the answer to this question.  I think it is important to know whether Chromium 3 (less carcinogenic material than Chromium 6) is oxidized from Chromium 6 (highly toxic) or not.

These 3  posts pose all of the questions that are bothersome to me re the long term systemic effects of Chromium, the immune system and carcinogenic effects.

Maybe no one knows the answer?