Ethics: November 2008 Archives

If history has taught us anything,* it's that rogue companies will substitute the renal toxin diethylene glycol (DEG) for the more-expensive glycerin in their products—regardless of the known, lethal consequences.

The latest incident involves a Nigerian drug manufacturer, which sold a DEG-contaminated teething formula ("My Pikin") that killed 25 infants and led to the hospitalization of 10 others, according to Reuters. Reports of possible contamination began 1 week ago, and the government has since shut down the responsible company, Barewa Pharmaceuticals, in Lagos.

A list of previous discoveries of DEG in consumer goods:

• Last year, Chinese-made toothpaste was found to be contaminated with low levels of DEG. The tubes, some of which were marketed for pediatric use, were found throughout Latin America, Canada, and the United States. Most of the contaminated toothpaste in the United States was imported through Long Beach, CA. Approximately 78,000 tubes were sold and distributed by at least one importer between December 2005 and May 2007 to prisons, luxury hotels, hospitals, and discount stores. In March of this year, a Los Angeles city attorney filed criminal charges against executives from 2 LA-based importers of the tainted toothpaste. However, it is believed that the low concentration of DEG in the toothpaste, which is unlikely to be consumed in significant quantities, did not result in reportable adverse events.
• In 2006, more than 100 Panamanians died after consuming cough syrup made with contaminated Chinese glycerin. The NYT traced 46 barrels of imported glycerin stock, labeled as 99.5% pure but containing ~24% DEG, from a Panamanian port to Spain to the Taxing Glycerine Factory in the Yangtze Delta.
• In 1998, 36 Indian children developed acute renal failure after consuming a DEG-tainted cough syrup (17.5%), which was produced by a company in Gurgaon; 33 of the children died.
• Between the fall of 1995 and July 1996, 109 children in Haiti experienced acute renal failure after consuming a locally made acetaminophen syrup that was tainted with DEG (14.4%); 91 children died.
• Beginning in 1990 and for several years thereafter, unexplained renal failure was identified in several hundred Bengalese children; 70% died in hospital. Renal failure was believed to be due to the ingestion of paracetamol elixir that was contaminated with DEG.
• In 1990, 47 children died in Nigeria (again) after ingesting paracetamol syrup that was contaminated with DEG.
• In 1986, 14 hospital inpatients died in India after being given glycerol that was contaminated with DEG (18.5%).
• In 1937, more than 100 US citizens—many children—died after consuming Elixir Sulfanilamide, a raspberry-flavored antibiotic syrup manufactured by the S. E. Massengill Pharmaceutical Company of Bristol, TN. The difficult-to-dissolve antibiotic was mixed with DEG by the company's head chemist, Harold Cole Watkins, who reportedly tested the elixir only for its appearance and palatability. The catastrophic event led to the passage of the 1938 Federal Food, Drug, and Cosmetic Act.

While frequently, but mistakenly, described as a component of engine coolants, DEG is chemically related to a common antifreeze ingredient, ethylene glycol. DEG is a cheap substitute for glycerin in the manufacture of consumer products.

HT: Pharmalot

* Other than, "you can kill anybody," according to Michael Corleone in The Godfather: Part II.

Picture of bottle of DEG-tainted Elixir Sulfanilamide from the FDA.

Today's Seattle Times provides a multi-part, if anecdotally ridden, expose of the MRSA scourge in Washington state (HT to the WSJ Health Blog). As in other states, the number of inpatients with the resistant bug has shot up dramatically during the last 10 years.

Measures to prevent and control MRSA infection in Washington hospitals, particularly in surgical patients, include prescreening for the bacterium. However, universal screening for MRSA is impractical at most hospitals, because of added costs and the extra work load imposed on already overtaxed personnel. Some hospitals, the Times reports, use selective screening programs, often inconsistently. One Washington hospital only screens for MRSA in elective-surgery patients; another only screens ICU patients; and another still only screens premature infants.

In this month's issue of the Journal of the American College of Surgeons, Swiss investigators report a more judicious model for screening hospital patients to prevent the nosocomial spread of MRSA. In their prospective study of more than 13,000 patients admitted for surgery, 3 independent factors correlated with MRSA carriage: recent antibiotic treatment, history of hospitalization within the last year, and age older than 75 years.

MRSA Risk Factor	Adjusted Odds Ratio	P Value
Recent antibiotic treatment (<6 months)	4.5	.001
History of hospitalization within last 12 months	2.7	.03
Age >75 y	1.9	.048

The investigators then calculated a score, from 0 to 9, to assess the probability of previously unknown MRSA. Two points were given for age older than 75 years; 3 for previous hospitalization; and 4 for recent antibiotic treatment.

Score	Probability of MRSA Carriage
<2	5%
2-6	11%
≥7	34%

Screening patients with all 3 risk factors would have identified approximately 40%-50% of MRSA carriers, according to the investigators. Notably, most MRSA-positive patients (64%) had not been previously identified as MRSA carriers, and their status would have been missed without testing on admission. While not perfect, this model allows for discriminatory MRSA screening in presurgical inpatients, when universal surveillance is not feasible.

MRSA = methicillin-resistant Staphylococcus aureus.

Scanning electron photomicrograph of MRSA from the CDC (magnification 9560x).

This fall, outbreaks of the vaccine-preventable illness whooping cough (pertussis) have hit counties in Illinois, Iowa, Missouri, Minnesota, Ohio, Nebraska, and South Dakota. The latest outbreak is in Evanston, IL, just north of Chicago, where 5 cases have been confirmed and 2 are suspected, all in children younger than 12 years of age who attend different schools. In Winnebago County, IL, 38 cases of pertussis have been reported since July 1. The county reported 8 cases last year. (11/14/08 addendum: In another northern IL county, McHenry, 4 cases of pertussis during the last month were just reported.)

Since September 1, 43 cases of pertussis have been reported in Springfield, OH. The ages of those affected range from 2 months to 74 years; however, most cases have occurred in children aged 7-10 years. In 2007, 4 cases of whooping cough were documented in Clark County, OH, and 7 occurred in 2006. A report earlier this month indicates that 631 cases of pertussis have occurred in the state this year, as of November 8.

A total of 27 pertussis cases, mostly in children, were reported in 8 counties throughout South Dakota during the last month. In Nebraska, 125 cases of the disease have been confirmed so far this year, with 48 recent cases in the area of Omaha and 5 in distant Lincoln County. In 2007, 70 cases of pertussis were reported in the entire state. More than a dozen people have been diagnosed in Clarke County, IA, with pertussis, and an unspecified number of cases of whooping cough have occurred this fall in west-central Minnesota.

Outside of the Midwest, recent pertussis outbreaks have been reported in North Carolina, Arkansas, Tennessee, Kentucky, New York, and Texas. High schoolers and adults have been affected, as well as children and infants. Older individuals typically have milder disease, but they serve as a vehicle for transmission of the infectious agent to the less protected (see news video here). Those most susceptible to pertussis complications are children younger than 12 months of age and those who are incompletely immunized. According to the CDC, the incidence of pertussis has increased steadily in the United States since the 1980s.

Pertussis is highly contagious, and human-to-human transmission occurs by means of respiratory droplets. The CDC indicates that the average incubation period of the bacterium is 7-10 days, but may be longer. For 1-2 weeks, nonspecific upper respiratory symptoms are typical (excepting some infants), followed by development of the characteristic, paroxysmal whooping cough, which can persist for 2-6 weeks. Vomiting and syncope may accompany the powerful cough, particularly in children. Common complications of the cough include pneumothorax, epistaxis, subconjunctival hemorrhage, subdural hematoma, hernia, rectal prolapse, urinary incontinence, and rib fracture. Antibiotic treatment (eg, erythromycin) of pertussis primarily mitigates spread of the disease. Convalescence, with a nonparoxysmal cough, may take another 2-6 weeks or longer. Affected individuals are susceptible to superimposed viral or other bacterial respiratory infections.

Immunity against the causative agent, the bacterium Bordetella pertussis, is obtained through vaccination; although protection is not absolute.* The DTaP vaccine is administered at 2, 4, 6, and 15-18 months of age and at 4-6 years of age. The Tdap vaccine is recommended at 11 or 12 years of age and in place of at least one 10-year tetanus booster between the ages of 19 and 64 years. A study published in this month's Pediatrics indicates that giving the first DTaP vaccine dose at 6 weeks, instead of 2 months, would prevent approximately 1200 cases of the disease, nearly 900 related hospitalizations, and 7 deaths.

DTaP = diphtheria, tetanus, acellular pertussis; Tdap = tetanus, reduced dose of diphtheria, reduced dose of acellular pertussis.

* According to a CDC report from 2005, pertussis vaccine effectiveness is 84% with 1 or 2 doses, 96% with 3 doses, and 98% with 4 or more doses. Vaccine effectiveness may be enhanced in persons who receive more than 1 type of vaccine (ie, DTP for doses 1-3 and DTaP for dose 4).

Picture of boy diagnosed with pertussis, aka whooping cough, from the CDC.

Addendum: A comparison of monthly data for reported pertussis cases in 2006 and the Google Trends feature for the same year (search terms, "pertussis" and "whooping cough") suggests that the Google feature works better for tracking influenza.

What's the difference between getting measles and getting married? You can do both in Gibraltar. No wait, that's what's the same. Okay, one results in an uncomfortable, highly contagious condition with the risk of long-term complications, and the other...Oh, forget it.

Nearly 1% of Gibraltar's population has been affected by an intense measles outbreak during the last 3 months, reports the NYT. Specifically 276 cases of the disease, among a population of 28,000, are being reported by the British territory's health director. A Gibraltar news source indicates that the actual number of those infected is probably greater, given that residents with mild disease may not report their illness.

Those with measles range in age from 4 months to 58 years; however, most are children. Cases have been generally mild, but some infected individuals—including infants—have needed intensive hospital care. Gene analysis suggests that the responsible virus came from an outbreak in nearby Algeciras, Spain, a port city across the Bay of Gibraltar, writes the NYT.

The recent number of measles cases in Gibraltar stands in sharp contrast to reported cases of the disease in the territory during the previous 10 years: zero. The outbreak is believed to be due to inadequate immunization, despite assumptions that vaccination rates among Gibraltar's children were high. All infected persons had not been vaccinated or were only partly vaccinated (ie, with 1 dose of MMR vaccine) reports a Gibraltar news source. During the beginning of the outbreak, a vaccination campaign faltered twice because of vaccine shortages in Britain, according to the NYT.

Earlier this year, measles was declared endemic in the United Kingdom, after 14 years of eradication. The UK's Health Protection Agency reports a total of 956 measles cases from January to September of this year. At last count, the number of measles cases in the United States for the year was 131.

Photo of child with measles rash from the CDC.

Here's the impression: As much as Steven Nissen, head of cardiology at the Cleveland Clinic, hates the cholesterol-lowering combo pill Vytorin (ezetemibe/simvastatin; Merck/Schering-Plough), he adores the statin Crestor (rosuvastatin), or its maker AstraZeneca, or both. The evidence is in a string of loving quotes from Nissen in the lay press about the positive results of the company's JUPITER study, which were concurrently presented at the ongoing Scientific Sessions of the AHA and published in the latest issue of the NEJM.

Nissen tells Bloomberg, "This may be the most important trial we've seen in a decade," and that the study findings are an "out-of-the-park home run."

He tells the LA Times, "It's a blockbuster. It's absolutely paradigm shifting."

He tells CNN, "This is a huge reduction, unprecedented reduction in risk occurring very quickly."

He tells Forbes, "It's potentially a game-changer."

He tells Time, "This is unprecedented...I have never seen a result of this magnitude reduction in risk. The results were significant enough to stop the study 3 years early."

He tells The Washington Post, "It's a breakthrough study," and "This changes medical practice in a major way. People are going to flock to their doctors to get their [c-reactive protein] measured and if it's elevated, they will say, 'Here, this drug you can take.' We'll save many lives and a lot of money."

He tells USA Today, "This is going to have huge repercussions. It means that men over 50 and women over 60 are going to get their [c-reactive protein] checked, and if they're high, they're going to get 20 milligrams of rosuvastatin...We know that we can reduce their risk of heart attack and stroke and angioplasty by nearly 50%. We've never seen this magnitude of risk reduction in a statin trial."

What's got Nissen (who was not a part of the JUPITER study, but who has received research support from AstraZeneca) so buzzed is that rosuvastatin 20 mg daily, when compared with placebo, reduced the relative risk of the primary endpoint, a first major cardiovascular event,* by nearly 50% in more than 17,000 men or women with nonelevated LDL levels but with high c-reactive protein (CRP) levels. The median follow-up of the study was 1.9 years, and the trial was stopped early because of the favorable results.

But despite the high relative risk reductions observed in the JUPITER study, absolute risk reductions were small:

• Rate of primary endpoint: rosuvastatin, 1.6%; placebo, 2.8% → difference, 1.2%.
• Rate of fatal or nonfatal MI: rosuvastatin, 0.35%; placebo, 0.76% → difference, 0.41%.
• Rate of fatal or nonfatal stroke: rosuvastatin, 0.37%; placebo, 0.72% → difference, 0.35%.

Patients who received rosuvastatin also demonstrated a significantly higher rate of physician-reported diabetes (but not myopathy or cancer): rosuvastatin, 3.0%; placebo, 2.4% → difference, 0.6%. Nissen's evidently nowhere near as worried about this adverse event (which undoubtedly raises CV risk) as he was about the possibly fluky cancer risk in the SEAS trial of Vytorin.  

The rationale for the JUPITER study is based on the proposed CV risk associated with high levels of CRP, an inflammatory biomarker and a proposed, independent predictor of vascular events. The lead author of the study, Paul Ridker, is coinventor of a patent (USP no. 7,030,152, along with Charles Hennekens) that describes the use of CRP to evaluate the risk of CV disease.

Other cardiologists, quoted in the press, are more cautious than Nissen about the JUPITER study results and the utility of measuring CRP.

Lori Mosca of Columbia tells Bloomberg, "This finding is clearly expanding the universe of who should receive cholesterol pills, but we need to carefully evaluate at what point it becomes cost-effective to treat the majority of people."

In an NEJM editorial, Mark Hlatky of Stanford writes, "Long-term safety is clearly important in considering committing low-risk subjects without clinical disease to 20 years or more of drug treatment," and adds that the daily cost of rosuvastatin, $3.45, is much higher than that of generic statins.

To this last point, others, like Northwestern's Robert Bonow and Public Citizen's Sidney Wolfe, believe that the JUPITER results can probably be generalized to all statins, including generic versions. AHA president Tim Gardner agrees: "This is a win for all statins," he tells the LA Times and predicts that the findings will be incorporated into practice guidelines.

Of course, the use of a statin in this context depends on the CRP level, which has a checkered history in clinical practice. "When the first [CRP] studies came out," ACC president Douglas Weaver tells Time, "a lot of us measured CRP. Then it fell out of vogue because there was nothing we could do with the result." Scott Grundy of Southwestern advises the New York Times, "CRP is not a standard test that everyone should have," and Daniel Rader of the University of Pennsylvania tells the paper, "It is an additional test that you should do if you're on the fence." Online sources (example) indicate that the cost of high-sensitivity CRP testing is approximately $50.

However, Nissen's (and AstraZeneca's) biggest buzzkill may be found in form of Sanjay Kaul from Cedars-Sinai, who tells Forbes, "I'm convinced CRP is a fad. Maybe there will be a little blip in its use, but many physicians have given up on CRP."

11/10/08 afternoon addendum: Polling results at the NEJM indicate an approximate 50-50 split among responders about whether the JUPITER results should change 1) the approach to laboratory screening and 2) the therapeutic use of statins.

* Nonfatal MI, nonfatal stroke, arterial revascularization, hospitalization for unstable angina, or confirmed death from CV causes.

ACC = American College of Cardiology; AHA = American Heart Association; CV = cardiovascular; JUPITER = Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; SEAS = Simvastatin and Ezetimibe in Aortic Stenosis.

2006 photo of Steven Nissen testifying at the Hearing on Building a 21st Century FDA.

In a show of institutional wisdom, the NIMH recently scrapped the idea of studying chelation therapy in autistic children. The study would have been the first well-controlled trial in autistic children of the treatment, which has been used largely on the QT and based on the unfounded idea that autism is caused by environmental mercury poisoning.

Published effects of chelation in autistic individuals (according to a PubMed search) are confined to case reports and letters—which, in some instances, reveal serious adverse effects, including death, of the therapy. A recent case report from The Netherlands described the development of Stevens-Johnson syndrome with oral DMPS therapy (eg, Unithiol, Dimaval, Mercuval) in an asymptomatic 11-year-old boy exposed to mercury vapor.

In 2005, a 5-year-old autistic British boy died after undergoing chelation therapy (Na2EDTA or edatate disodium 990 mg) by IV push in the office of US physician Roy Kerry. The cause of death was cardiac death due to hypocalcemia. (Addendum: This case was presented online last month in Clinical Toxicology.) Also that year, a 2-year-old girl with lead poisoning died of chelation-induced hypocalcemia, due to the unintentional administration of Na2EDTA (Endrate; Hospira) instead of the ordered CaNa2EDTA (edatate calcium disodium or Calcium Disodium Versenate; 3M) in a Texas hospital. In 2003, a 53-year-old woman in Oregon died of cardiac arrest due to hypocalcemia after receiving an unspecified EDTA compound, 1500 mg, by IV push. The chelator, prescribed by a naturopathic physician, was intended to remove heavy metals. (These deaths were also reported in the MMWR.)

According to Brown et al (2006), CaNa2EDTA (which is a nonspecific metal chelator) and another chelator, succimer (DMSA or Chemet; Ovation), are unlikely causes of hypocalcemia. Na2EDTA, however, "should never be used for treating lead or other heavy metal poisoning in children because it induces hypocalcemia, which can lead to tetany and death." According to the prescribing information, Na2EDTA is "indicated in selected patients for the emergency treatment of hypercalcemia and for the control of ventricular arrhythmias associated with digitalis toxicity." Earlier this year, the FDA issued a public health advisory regarding confusion between Na2EDTA and CaNa2EDTA and recommended the use of newer alternatives for Na2EDTA indications.

In the 2007 case series of Mark and David Geier (which shows up in a PubMed search for trials or case reports, using the words "autism" and "chelation"), DMSA or DMPS was administered to 8 children (at 3-14 years of age), most often as "provocation" or "challenge" doses. The amounts of DMSA or DMPS administered in these cases are not specified. Three children (at 3, 5, and 5 years of age) received "therapy" or a "treatment course" with DMSA or DMPS. Dosages prescribed and the durations of therapy in these cases are also not specified by the Geiers. Chelation was most often administered orally; although a 5-year-old child received a "provocation dose" of DMSA by suppository, and a 3-year-old child and a 5-year-old child received DMPS "therapy" transdermally.

Subject		Chelation Therapy	Route of Administration
1	@ 5 years	"Provocation dose" of DMPS	Oral
2	@ 5 years	"Provocation dose" of DMSA "Provocation dose" of DMPS	Suppository Oral
3	@ 4 years @ 5 years	DMSA "challenge" DMSA "therapy"	Oral Not described
4	@ 3 years @ 5 years	"Provocation" DMSA DMPS "therapy"	Oral Transdermal
5	@ 5 years @ 6 years	"Provocation dose" of DMSA "Provocation dose" of DMSA	Oral Oral
6	@ 6 years	"Provocation dose" of DMSA	Oral
7	@ 14 years	DMPS "challenge"	Oral
8	@ 3 years	"Treatment course" of DMSA "Treatment course" of DMPS	Oral Transdermal

According to the Chemet (DMSA or succimer) prescribing information, the drug "is indicated for the treatment of lead poisoning in pediatric patients with blood lead levels above 45 μg/dL." So-called provocation or challenge doses of the drug are not described. (A PubMed search reveals articles about the provocative use of chelating agents in the setting of lead exposure only—eg, Lee et al, 1995.) The drug is administered orally and on the basis of the child's weight. A course of treatment lasts 19 days and may be repeated, depending on the blood concentration of lead. For children who cannot swallow capsules, the contents may be sprinkled on food. Although there is a lot of online discussion among autism groups about the use of DMSA as a suppository, the manufacturer evidently does not offer a suppository formulation or recommend suppository administration of the agent.

The branded forms of DMPS do not appear to have been reviewed or approved for use in the United States by the FDA. A 2004 letter from the company Heyltex (whose parent company in Germany makes Dimaval) reported cases of skin reactions to pharmacy-compounded versions of the drug for transdermal administration. Most important, the company indicated that it was unaware of any clinical data demonstrating the efficacy or safety of transdermal DMPS and recommended that the drug only be compounded for oral or injectable administration. (The absorption of transdermal DMPS has also been questioned by Orac.*) It is unclear how DMPS is obtained by US pharmacies for compounding; however, the drug may be freely available in Germany without a prescription, given its longstanding status there. (Addendum: In a 1999 issue of the Federal Register, the FDA proposed that DMPS be considered a bulk drug substance that may be used in pharmacy compounding, although the substance is not an FDA-approved drug. According to Anderson and Aaseth (2002),

DMPS is registered in Germany for treatment of mercury intoxication; however, it is not approved in the United States, so unless special permission is given by the US Food and Drug Administration, it is not lawful for physicians to use it in the United States, nor is it lawful for pharmacies to compound it. Still, DMPS is being illegally used by members of the alternative health industry to treat people allegedly suffering from mercury intoxication...)

There is no specific indication by the Geiers that treatment courses with chelation, 2 of which were administered transdermally (DMPS) and 1 of which was administered by an unidentified route (DMSA), directly affected clinical symptoms in their autistic subjects.

DMPS = 2,3-dimercapto-1-propanesulfonic acid; DMSA = dimercaptosuccinic acid; EDTA = ethylenediamine tetraacetic acid.

* The question of the absorption (and the consequent efficacy) of transdermal DMPS is especially important, because the Geiers reported "significantly elevated mercury levels" in the hair of a child who had received transdermal DMPS therapy and "significant concentrations of mercury" in the fecal sample of another child who had received transdermal DMPS therapy, suggesting that transdermal chelation promoted the excretion of mercury.

When examining the work of Mark and David Geier (and by extension, the work of their various coauthors), it becomes readily apparent that their rationales for administering Lupron and chelation therapy to children with autism are, at best, flimsy and, at worst, products of fantasy. It amounts to, in my mind, the twisted end-result of a highly convoluted, technically dense wish fulfillment that rests on these disturbing claims: 

1. That autism remains a consequence of mercury toxicity (despite a lack of evidence or, in fact, an abundance of contrary evidence);
2. That mercury toxicity can be indirectly established by measuring certain urinary porphyrins (on the basis of rat data and a pilot study in Mexican dental workers);
3. That questionable values of thiols indicate a reduced capacity to eliminate heavy metals generally and mercury specifically (on the basis of rat and crustacean data);
4. That mercury is bound up with testosterone in the human body (on the basis of an in vivo condition not found in living organisms); and
5. That children with autism demonstrate central precocious puberty* (in the absence of acknowledging and publicly documenting the diagnostic criteria for the condition).

At this blog, the values of some thiol levels in autistic children published by the Geiers have been questioned in a series of posts—perhaps too many (see, for example, here, here, here, here, here, here, and here). These questionable values undermine the validity of at least one of the Geiers' claims—namely, that thiol levels in autistic children (as the Geiers' indicators of a "reduced detoxification capacity") are significantly different from those in control children.

In a kind of preemptive rebuttal to this very legitimate concern, Geier et al wrote in their recently published article in the Journal of the Neurological Sciences:

It was observed, when comparing the actual numeric values from the current study with previous studies, that there were some differences in the actual values measured for the different metabolites examined. This may reflect differences in the exact methods employed in measuring various blood levels of transsulfuration metabolites [ie, thiol levels], but given the consistency observed between the studies, helps to indicate the overall validity of the observations.

In other words, Geier et al acknowledge that some of their thiol levels are inconsistent with those in other published sources—although they do not admit specifically that their values for plasma cysteine, oxidized glutathione (GSSG), and total sulfate are different by 1, 2, or 3 orders of magnitude from those in the cited literature. They also fail to note that at least 2 of their assay references provide very different values for plasma cysteine and total sulfate, respectively.

But, because Geier et al found statistical differences between autistic children and control children—like those in the work of James et al, for instance—they defend the validity of their findings. This is like saying that, although my measurements of blood pressure are 12/8 mm Hg or 1200/800 mg Hg, instead of 120/80 mm Hg, findings of statistical difference are still valid—which is, of course, rubbish.

And in cases in which the Geiers' thiol levels in autistic children fall within published reference ranges, they nevertheless appear eager to find statistical differences between these levels and those in control children—which violates the spirit of the null hypothesis. Generally such conclusions must be offered extremely cautiously and should require independent reproducibility before recommending costly diagnostic tests or therapies.

In addition, the published drawbacks of thiol testing in human plasma also raise concerns about the validity of the Geiers' conclusions. For instance, the reliability of measuring reduced glutathione (GSH) and GSSG in human plasma has been called into question. Values of these substances are relatively very low in human plasma and can vary substantially on the basis of specimen handling—for instance, they are reported to vary considerably with even minor hemolysis. One laboratory source indicates that it is not possible to distinguish between GSH and GSSG in serum or plasma, owing to their very low levels.

On a related note, there may be confusion about the presentation of values for blood GSH and those for plasma GSH in the Geiers' published work. In "A case series of children with apparent mercury toxic encephalopathies manifesting with clinical symptoms of regressive autistic disorder," which was published in the Journal of Toxicology and Environmental Health, Part A last year, the Geiers measured blood GSH in 5 children (age range, 4-9 years) and reported values from 18 to 28 mg/dL. This range is the same range reported for plasma GSH in 10 children by the Geiers in their 2006 Hormone Research article. To aid further examination of the Geiers' published values for blood or plasma GSH, these results are tabulated along with values from other sources (including other studies written by the Geiers). (Note that values, when necessary, are converted to units of μmol/L [molecular weight of GSH = 307.43 μg/μmol].)

Source	Blood GSH, μmol/L	Plasma GSH, μmol/L
Geier et al, 2008 (n = 28)	—	3.1 ± 0.53 (control, 4.2 ± 0.72)
Geier et al, 2008 (n = 38)	—	3.14 ± 0.56 (control, 4.2 ± 0.72)
TAP et al, 2008 (international patent application) (n = 2)	—	651* (lab ref, >1041)
ALPCO, 2008	620-970	—
Geier and Geier, 2007 (n = 5)	585-911 (lab ref, >1041)	—
Geier and Geier, 2007 (n = 1)	—	0.933 (lab ref, >2)
Rossi et al, 2006 (n = 4)	1323-1392	—
Geier and Geier, 2006 (n = 10)	—	585-911 (control, 911-1431)
James et al, 2006 (n = 80)	—	1.4 ± 0.5 (control, 2.2 ± 0.9)
Melnyk et al, 1999 (n = 11)	—	6.9 ± 0.5
Michelet et al, 1995 (n = 13)	—	3.57 ± 0.74
Andersson et al, 1993 (n = 10)	—	3.4 ± 0.9
Curello et al, 1987 (n = 27)	—	4.2

* This value (originally reported in mg/dL) is not specified to be from plasma in the patent application, but it is presented along with other plasma thiol levels.

The 5 blood GSH values (585-911 μmol/L) reported by the Geiers in their 2007 case series are reasonably consistent with reference values for blood GSH in the literature, and the reference value for plasma GSH in the 10-year-old boy (>2 μmol/L) is also reasonably consistent with the relevant literature (if plasma values of GSH are reliable at all). But the data also suggest that the plasma GSH values (585-911 μmol/L) reported by the Geiers in Hormone Research in 2006 and the GSH values provided in the international patent application may well be blood GSH values.

In the 2007 case series and the Hormone Research study, GSH values were measured at the dubious Great Smokies Diagnostic Laboratory, aka Genova Diagnostics in Asheville, NC. In a curious case of indirect self-reproach, Mark Geier more or less dismissed this laboratory in his recorded June 2007 speech in front of the CDC (@ the 3:26 mark on YouTube), approximately 1 year after his Hormone Research article was published and 1 month after his case series was published.

* And this is without even discussing the Geiers' use of Lupron in autistic children during timely puberty.