* "The American College of Preventive Medicine concludes that there is insufficient evidence to recommend routine population screening with DRE or PSA. Clinicians caring for men, especially African-American men and those with positive family histories, should provide information about potential benefits and risks of prostate cancer screening, and the limitations of current evidence for screening, in order to maximize informed decision making." This leaves the physician in the situation of avoiding biases about treatment options as well as the pros and cons; not always an easy position to be in. I had a urologist suggest surgery and two radiologists suggest radiation-one external beam and the other seed implants. Watchful waiting was hardly discussed. Am J Prev Med. 34:164-70, 2008.

* Results of this study of men aged 50-64 years (706 cases, 645 controls in Seattle) suggest a reduction in prostate cancer-specific mortality associated with PSA and/or DRE screening in middle-aged men. "The findings should be interpreted cautiously, however, as results are based on observational data. Further, the study was not able to separate the relative efficacy of PSA versus DRE screening." Cancer Causes Control. 18:931-7, 2007.

* Marcella was more emphatic when writing about the New Jersey experience: "PSA screening using an ever/never tabulation for tests from 1989 until 2000 did not protect New Jersey men from prostate cancer mortality." J Gen Intern Med. 23:248-53 2008.

* In the Tyrol region where treatment is freely available to all patients, where widespread PSA testing and treatment with curative intent occurs, there was a reduction in prostate cancer mortality rates which was significantly greater than the reduction in the rest of Austria. This reduction in prostate cancer mortality is most probably due to early detection, consequent down-staging and effective treatment of prostate cancer. BJU Int. 101:809-16., 2008.

* A single PSA test taken at or before age 50 is a very strong predictor of advanced prostate cancer diagnosed up to 25 years later. This suggests the possibility of using an early PSA test to risk-stratify patients so that men at highest risk are the focus of the most intensive screening efforts. BMC Med. 15:6, 2008.

* Active surveillance; a reasonable management alternative for patients with prostate cancer: The Miami experience. "Patients who are followed on AS must be selected using narrowly defined inclusion criteria and closely followed with a standard regimen of PSA testing, digital rectal examination and repeat biopsy." BJU Int. 101:165-9, 2008.

It would seem that little has changed in the past year-there is no consensus as whether to screen.  Leaving the physician and patient to discuss and decide. The patient has certain responsibilities to make himself (and those close to him) aware of the pros and cons of the various options. This seems to me to go beyond simply asking his GP or even the urologist.

In the United States, about 30,000 people suffer from HD. The estimated prevalence is about 1 in 10,000 persons, which is similar to that for PKU. More than 150,000 others have at least a 50:50 chance of developing the disease for which there is no cure.  Additional thousands may also develop the disease. 

HD is quite variable in its age of onset-the adult form most often shows its signs in middle age with the uncontrolled movements. Some HD termed juvenile onset begins before age 20, often by age 10.  In these cases, the symptoms may show as subtle changes in handwriting or muscle twitching. A few persons develop HD after age 55.  In these patients the diagnosis is often more difficult.

HD is a genetic disease resulting in degeneration of neurons in certain areas of the brain.  The gene for HD has been located on chromosome 4, one of the non-sexed linked genes.  HD, an autonomic dominant disorder, requires only one copy of the gene to be present to cause the disease. The mutation of the gene results in several base pairs-C, A and G-being repeated several dozen times. A child of a parent with HD has a 50:50 chance of inheriting HD. A child who inherits the gene and survives long enough will develop the HD, perhaps after having passed the gene onto one or more of his or her children. This is because most cases do not appear until the person has reached puberty and can conceive a child.  It is this aspect of the disease, differing from PKU, which can be diagnosed in the first few weeks of life that leads to the difficult decisions.

Woodie Guthrie, a folk singer and composer, died in 1967 after suffering from HD for 13 years. His son, Arlo, also a singer, is now 60 and has shown no signs of HD. Woody had been misdiagnosed, considered an alcoholic and was in and out of mental hospitals for a number of years. His case is not exceptional-HD is often missed.  It can usually be diagnosed correctly by an experienced neurologist. Today, thanks to the discovery in 1993 of the gene for HD, there is a laboratory test of the person's DNA. In this test the number of CAG base pairs (this triplet codes for glutamine) repeats in the region of the gene can be counted will be helpful in assessing the patient's risk for HD.  The gene where these repeats occur has been given the name huntingtin. The function of this protein is currently not known.

• Patients with no more than 28 repeats will not develop HD.
• Patients with 29 - 34 will not develop HD, but the next generation is at risk as the mutant gene appears to increase the number of repeats with each generation.
• In those with 35 - 39 repeat some, but not all, persons will develop HD, and the next generation will be at increased risk.
• Those patients with 40 or more repeats of CAG will develop HD.

In some cases a CT or MRI will be requested. These, though, are not specific for HD.

There is no treatment to stop or even slow the progression of this debilitating and fatal disease. Some antipsychotic and antidepressant drugs may reduce the symptoms of HD.  Over the past 20 years and quite recently cysteamine has been used as a treatment for the motor symptoms. This has met with limited success.

The decisions. Consider a person recently diagnosed with HD who also has children. These children carry a 50 percent chance of developing HD as well as transmitting the gene to their children. The decision the children have is whether to be tested to know if in the future (perhaps many years in the future) they will (or will not) develop HD. In addition, that test will indicate something about the risk of their children developing HD.  If the children of the patient are tested and found to carry the gene, they must decide whether to have children of their own. Today with in vitro fertilization it is possible to screen the embryos for HD and use only those that are do not carry the mutant gene. This scenario leads to another set of difficult practical, financial and ethical questions.

The children of the patient must decide whether to tell their spouse or spouse to be that they are a carrier of HD.

Consider the physician who may be asked to make the diagnosis. May a physician choose not to assist in such a diagnosis? Or at least not without a thorough discussion of the genetics of HD and the possible outcomes of the test, and the paths to take once the diagnosis is at hand? Is the physician obligated to tell the patient that a test exists for the children of the patient?

It is possible that sometimes our technology outruns our ability to deal with the answers and the new questions such technology forces us to consider.

Our modern efforts to produce artificial blood were spurred by the military in World Wars I and II and, more recently, by the discovery in the early 1980s that HIV could be transmitted by blood transfusion. If a liquid, or even a partial liquid, containing microparticles that could replace blood were available, completely safe and stable for long periods; it would be extremely useful in emergencies, disaster and wars-as well as in countries where blood is not collected and stored as it is in the U.S. and western Europe. In the U.S., for example, situations not usually associated with a need for artificial blood include patients with stroke (the third leading cause of death in the U.S.), where limited studies have shown that one form of artificial blood reduces long-term effects through the oxygenation of the tissues. Another example is sickle cell disease, which affects 100,000 Americans and as many as 50 million people in Africa (in parts of which HIV infection is endemic and donors are nearly non-existent and storage of blood is a severe problem).

Keep in mind that blood does many things. Currently the artificial blood being tested is designed to do only one of them: carry oxygen and carbon dioxide. No substitutes have been invented that can replace the other vital functions of blood: coagulation and immune defense. Thus, replacement solutions being developed today are more accurately described as oxygen carriers. There are basically two types of oxygen carriers, which differ in the way they transport oxygen. One is based on perfluorochemicals (PFC); the other based on hemoglobin.

The first are inert materials that can dissolve approximately 50 times more oxygen than blood plasma. These perfluorochemicals are inexpensive and fairly easy to produce and can be prepared completely free of biological materials; therefore, there is no risk of infectious agents contaminating them. In order to work, however, they must be combined with other materials that enable them to mix in with the bloodstream. These companion materials are fatty compounds known as lipids. They take the form of an emulsion, a suspension of extremely small particles in a liquid that can be injected into a patient. Improved versions of perfluorocarbon emulsions are being developed and are under various phases of FDA approved investigation. Hemoglobin-based oxygen carriers (HBOCs) utilize the same oxygen-carrying protein molecule found in blood. Oxygen bonds chemically to the hemoglobin, whereas it dissolves only into the PFC emulsions. HBOCs differ from red blood cells in that the hemoglobin is not contained within a membrane. The membrane of a red blood cell contains the antigen molecules that determine the type of the blood (A, B, AB or O). Because HBOCs have no membranes, they do not need to be cross-matched by type and can be given to any patient without previous testing. In addition, these artificial oxygen carriers can be stored for long periods, greatly simplifying the work of the blood bank. Best of all, HBOCs can be used in situations and locations where real blood is not available, as at disaster sites, underdeveloped countries or battle zones.

Two main problems arise when hemoglobin is removed from the red blood cells; these problems account for the large amount of scientific research that has been conducted so far in this area. First, the red cell membrane protects hemoglobin from degradation and protects tissues from the toxic effects of free hemoglobin. Second, when oxygen is being delivered by a cell-free carrier instead of red blood cells, complex biological mechanisms alter the flow through the smallest blood vessels (the arterioles and capillaries). Major advances have been made in overcoming both of these problems, and several HBOC products are now in advanced human trials. It is anticipated that in the next one to two years the first of these products will become available to physicians for use in patients.

While PFC's may never eliminate the practice of blood transfusion or be approved as a blood substitute, they do hold a great deal of potential for other applications. They could be incorporated into solutions used in open heart surgery, and in supplying devascularized organs with oxygen prior to transplantation. Along those same lines, they could be used to perfuse the myocardium or brain tissue in heart attacks and strokes, oxygenating obstructed regions due to blockage and hopefully improving survival and recovery.

Another possible area of application is in cancer therapy. PFC's could increase the oxygenation of tumors, consequently benefiting radiation and/or chemotherapy in cancer treatment. Chemotherapeutic drugs could be added to the PFC and carried along to the site of the cancer. Also, local application of toxic doses of PFC resulted in the necrosis of cancer cells. This is especially promising in the treatment of cancers of the head and neck regions, which are currently difficult to treat.

Other possible applications include the treatment of fungal/bacterial skin and GI tract infections, oxygen deficient conditions (i.e. carbon monoxide poisoning), Alzheimer's disease and medical imaging.

Infection is extremely common in young women in their first decade of sexual activity. Persistent infections and precancer are established, typically within 5-10 years, from less than 10 percent of new infections. Invasive cancer arises over many years, even decades, in a minority of women with precancer, with a peak or plateau in risk at about 35-55 years of age.

Each genotype of HPV acts as an independent infection, with differing carcinogenic risks linked to evolutionary species.

A recent meta-analysis of more than 450 reports of HPV vaccine by a group in Ottawa found that among women aged 15-25 years not previously infected with vaccine-type HPV strains, prophylactic HPV vaccination appears to be highly efficacious in preventing HPV infection and precancerous cervical disease. They did suggest that "long-term follow-up is needed to substantiate reductions in cervical cancer incidence and mortality." L. Rambout et al. CMAJ. 2007 177:469-79. 2007.

The FDA has approved Gardasil, a vaccine that prevents several strands of the sexually transmitted disease HPV. The vaccine is approved for women ages 9-26 to prevent cervical cancer and genital warts caused by HPV types 6, 11, 16 and 18.

Texas governor Rick Perry (R) has issued an executive order making Texas the first state to require girls entering the sixth grade to receive the HPV vaccine, beginning in September 2008.  (Texas has the second highest number of women with cervical cancer in the country. Governor Perry pointed out in his executive order that there were 1,169 new cases and 391 deaths from cervical cancer in Texas in 2006.)

Conservatives called on Perry to reverse his arguing that the mandate makes sex seem permissible and that parents should be the ones to decide whether to immunize their daughters.  One legislator raised the question of what the vaccine would cost the state (was the cost of the vaccine being weighed against the cost of treating CC, not to mention the loss of life CC causes?)

Several Texas lawmakers expressed outrage at Perry for circumventing the legislative process.

The only ‘right' answer might be the one a person chooses.  However, any choice should be an informed one.

Here are some (by no means all) aspects of the discussion to consider as you think about taking a position:

• Adult stem cell research has been going on for nearly 40 years. Embryonic stem cells (ESC) were discovered only in 1998, barely 10 years ago.
• Approximately 60 percent of embryos created in an IVF system are not suitable to develop into a full term healthy baby; therefore, the majority of embryos in an IVF program are excess and will not be used.
• In most cases of natural conception, about 65 percent of the fertilized eggs will lead to a fetus that has even a chance of developing.
• Prior to the 19^th century, the Catholic Church adhered to the thinking that a soul emerges at 40 days gestation for males and 80 days for females.
• Peter Nord of the Presbytery of Baltimore, an arm of the Presbyterian Church, states, "The current Catholic understanding of the beginning of life seems to somehow become the gold standard by which everything is judged.... Most of us support the use of embryos that would otherwise be discarded." This is also the general view of most of the Jewish denominations as well as for Muslims (Human life for them posits that human life begins at 120 days after conception).
• As a single example of the polarity of this ‘discussion' let me cite two views on the treatment, if not to say cure, for juvenile diabetes (Type I). These two positions seems to be related to science. On the one hand is Robert Goldstein from the Juvenile Diabetes Research Foundation who testified before a senate committee hearing in 2004 and stated firmly that the JDRF will continue to support ESC research. On the other side is Dave Andrusko from the National Right to Life organization. He writes of work done by a group at Harvard and Massachusetts General Hospital that cured Type I diabetes in mice using an immune system hormone without recourse to any stem cells.

Turning to the ethical question, David Prentice has written for the Family Research Council whereby he discusses therapeutic cloning. To him, therapeutic cloning is "obviously not therapeutic for the [cloned] embryo. The new human (my emphasis) is specifically created in order to be destroyed as a source of tissue." (See Jodi Piccoult's book My Sister's Keeper). Contrary to this position is that taken by Jonathan Moreno and Sam Berger writing in the American Journal of Bioethics.  "ESC research is morally permissible because, although embryos deserve respect, they are not morally equivalent to human beings."

An excellent place to begin reading on this subject is the Stem Cell volume in the Opposing Viewpoints series.

"If an influenza pandemic occurs, it is expected to have dire consequences, including millions of deaths, social disruption, and enormous economic consequences. The Department of Health and Human Resources plan, released in November 2005, clearly affirms the threat of a pandemic."  (Mody L, Cinti S. J Am Geriatr Soc. 2007 Sep;55(9):1431-7.)

I have looked a bit further into the question of a new outbreak of influenza and want to share some of what I have found. 

During the period from May 20 to September 15, 2007, WHO and NREVSS collaborating laboratories in the United States tested 21,029 respiratory specimens for influenza viruses; 398 (1.9%) were positive. Of these, 330 (83%) were influenza A viruses, and 68 (17%) were influenza B viruses. Of the influenza A viruses, 152 were subtyped: 67 (44%) were influenza A (H1) viruses, and 85 (56%) were influenza A (H3) viruses. Influenza viruses were reported from 22 states in eight of the nine public health surveillance regions. However, 200 (50%) of all the influenza viruses, including 63 (94%) of the 67 influenza A (H1) viruses, were reported from Hawaii, and 100 (25%) were reported from Florida.

Migratory birds and, less likely, bird trafficking are believed to be extending the avian influenza A/H5N1 globally.  More than 200 human cases of avian influenza virus infection due to A/H5, A/H7, and A/H9 subtypes mainly as a result of poultry-to-human transmission have been reported with a greater than 50% case fatality rate for A/H5N1 infections. A mutant virus capable of efficient human-to-human transmission could trigger another influenza pandemic. 

There does seem to be a question of how these viruses are transmitted.  From 21 March through 3 April 2006, 295 poultry workers and 25 laboratory workers with suspected exposure to H5N1 virus were administered a questionnaire to assess H5N1 exposures, medical history, and health care utilization.  A serum specimen was collected from participants to test for H5N1 neutralizing antibodies by microneutralization assay.  The 295 poultry workers reported a median of 14 days of exposure to suspected or confirmed H5N1-infected poultry without antiviral chemoprophylaxis and with minimal personal protective equipment.  Among 25 laboratory workers, all handled poultry specimens with suspected H5N1 virus infection. All participants tested negative for H5N1 neutralizing antibodies.

Relating to the transmission of avian virus to human a study to assess the molecular characterization of H5N1 viruses from Thailand showed that there were no significant point mutations in the critical regions, and there was no evidence of changes in the viruses that indicate they are capable of sustained human-to-human transmission.

How to prevent an outbreak has also been the subject of some discussion.  Increased attention to prophylaxis against viral infection has identified several potentially complementary approaches: nonpharmacologic measures (e.g., travel restrictions), vaccination, chemotherapeutic agents, and herbal/natural products. All have significant limitations that point out the need for additional. Herbal/natural products, particularly those based on green tea extract, offer promise as adjuncts or alternatives to current interventions and warrant further evaluation in well-controlled human trials.

Should an outbreak occur it is expected to have dire consequences, including millions of deaths, social disruption, and enormous economic consequences. The Department of Health and Human Resources plan, released in November 2005, clearly affirms the threat of a pandemic.  Anticipating a disruption in many factions of society, every segment of the healthcare industry, including nursing homes, will be affected and will need to be self-sufficient. Disruption of vaccine distribution during the seasonal influenza vaccine shortage during the 2004/05 influenza season is but one example of erratic emergency planning.  I can confirm a shortage of ‘flu shots' in my area in November-December 2007. 

I'd be interested in having some of your comments on your own institution's preparations for an influx of ‘flu' patients, what the community's thoughts are on making plans and your own thoughts on the issues surrounding a possible if not inevitable epidemic.

Another project to assess how effective cTn was when measured in the ED also showed that the length of stay was significantly reduced: 5.2 hours versus 7.1 hours. POC was significantly shorter (average15 minutes) than for central laboratory testing (83 minutes). With central testing as the criterion standard, POCT had a sensitivity of 100 percent and a specificity of 96 percent. (Singer AJ, Ardise J, and Gulla J. Ann Emerg Med 45:587-91, 2005.)

There is another area of cTn testing I'd like to mention. Since the original cTnI assays were introduced over a decade ago, the low-end precision (detectability, sensitivity) of them has improved markedly. In the beginning we were reluctant to talk much about cTn and cell injury and risk for future events (vs. cell death and MI). However, the improved precision has allowed us to use cTn assays in these areas.

Patients who present with chest pain-in whom unstable coronary disease is possible but not overt-are at higher risk of cardiac events if troponin is elevated. Even those patients with non-ST-elevation acute coronary syndrome, any troponin elevation is associated with an increased risk for cardiovascular events.

In a study involving patients who presented with chest pain but who had normal ECGs, coronary artery disease was found in 90 percent of those with an elevated troponin level (> 0.2 ng/mL) and in 23 percent of those with a normal troponin level. Had the 99th percentile been used instead of usual cut-off value for the troponin levels, even more patients with coronary artery disease would likely have been identified. (DeFilippi CR, Tocchi M, Parmar RJ, et al. J Am Coll Cardiol 2000;35:1827-34.)

Quite recently cardiac troponin I (cTnI) was measured in 1092 stabilized ACS patients at 6 weeks, then at 3 months and 6 months after enrollment. The authors noted that "persistent minor cTnI elevation can be detected frequently in patients stabilized after an episode of non-ST-elevation acute coronary syndrome with the use of a sensitive assay. Elevated cTnI levels >0.01 microg/L predict mortality during long-term follow-up. Our results emphasize the importance of further troponin testing in non-ST-elevation acute coronary syndrome patients after hospital discharge." (Eggers KM, Lagerqvist B, Venge P. et al. Circulation. 116:1907-14.)

A recent study compared a first generation cTnT (detection limit < 0.01 ng/mL) with a new more sensitive assay (< 0.001 ng/mL) in 4053 patients with chronic HF. Troponin T was detectable in 10.4 percent of the population with the older cTnT assay compared with 92.0 percent with new assay when using the median (0.012 ng/mL) as the cut-off. This group had more severe HF and worse outcome. (Latini R, Masson S, Anand IS, Circulation.116(11):1242-9. 2007)

These and other studies have found value using the more sensitive assays with a cut-off at the 99th percentile or as in the last example, above the median. Often these patients have no ECG abnormalities and even ‘normal' catheritzation results. However, that does not preclude the patient from being at risk for an event. The laboratory needs to aid the clinician in understanding the significance of these low values and work with the staff on how best to triage them.

We are fortunate in the laboratory to have assays for cardiac troponin I and T (cTn) that can be performed on a sample (whole blood, serum or plasma) in 10 to 20 minutes. This has been a boon to many ED clinicians, especially in those MI patients whose ECGs are not diagnostic-as many as 50 percent. These assays are utilized in two versions, which for the sake of our discussion I will term simply laboratory-based (lab), and near patient (POC). Just having mentioned POC has raised the hackles on many of you, perhaps for good reason. I have often shied away from the discussion of where cTn testing should be done. However, I recently had the opportunity to listen to an ED physician described 10 years (sic) experience with cTn testing in his ED (POC). His busy ED is in a mid-sized community hospital. The nurses perform the test just as they have been doing ECGs for decades. There was reluctance when the project began but the entire staff soon saw the benefit in terms or early treatment for the patient with an MI (perhaps as low as 10 percent of patients in an ED with chest pain). Those without MI could be more rapidly triaged home or to a less intense bed. This laboratory has shown improvement not only in turn around times, a reduced length of stay in the ED, but a cost savings for the hospital. Having cTn available rapidly in the ED allowed the clinician and the nurses to be more effective as the assay allowed them to allocate their time better. As you can easily infer, my thinking on the question of where to test for cTn has changed.

The curve (Everett M. Rogers, Diffusion of Innovations, 1962) illustrates the idea of adoption of innovation. The area to the line on the far right shows those who are the last to accept innovation. The area between lines 1 and 2 indicates those who are slow to adopt innovation; between 2 and 3 are the earlier adopters; between 3 and 4 are those on the leading edge, while those to the left of 4 are the inventors and innovators themselves. Most of us cannot be in that last group, but it concerns me that many of us are in the groups to the right of line 3. Over the last three decades  a number of folks like Zoe Brooks, Jim Westgard, Neill Carey, Michael Toyashima and me (if you will) have been promoting a QA system or a part of a system for detecting analytical errors in laboratory instruments. This system was proposed in the 1970s by CAP and AACC (first in articles in Clinical Chemistry, then as a proposed method by Dr. Westgard). This approach (often referred to as "The Westgard Rules") has never been shown not to work. I have been fortunate to work with quite a number of laboratories who have adopted this system and have demonstrated that it is cost-effective and reduces turn around time and often length of stay; thus, lowering overall frustration.  Yet, there are still a surprising number of laboratories that remain to the right of line 1-who have yet to accept this tool. As our instruments become more precise and helpful in detecting errors and our LIS/HIS/middleware become more sophisticated at helping detect errors, it seems that there are now even better reasons to move to the left side of the curve and adopt a quality monitoring system that was once innovative and now should be a part of every QA system. There are many tools available to help with this move. I would welcome the opportunity-as would the others I mention above-to share some of them with you.