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British researchers are reporting success creating human primordial germ cells (the precursors of egg and sperm) from embryonic stem cells.

Reuters has the story:

“We’ve shown we can generate primordial germ cells. These are the cells that go on to form either the sperm or the egg depending on the gender of the individual,” said Professor Harry Moore, a reproductive biologist at the University of Sheffield in England.

“In culture, we’ve been able to show, using human embryonic stem cells, that some of those cells develop further to a later stage of sperm development,” he told Reuters.

Possible cure for infertility? In addition to making babies, eggs are the raw material for making new embryonic stem cell lines. The application of this work to making eggs could eliminate the problems of limited egg donation. It also will raise issues for the anti-embryonic-stem cell position: do embryos made completely from in vitro grown cells still count as “human life”?

Posted by rikurzhen at 06:22 PM

• Category: Science 
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A new paper, ,“The Opportunity Cost of Admission Preferences at Elite Universities,” quantifies the effect that eliminating racial preferences would have on the demographics of elite universities. The advertised conclusions come as no surprise to me: (1) it would greatly reduce the number of black and Hispanic students and (2) it would not greatly increase the admit rate for white students. What blows me away is the effect on Asian admissions: 80% of the spaces taken by affirmative action would go to Asian students.

Disregarding race in college admissions would cause sharp drops in the number of black and Hispanic students at elite institutions, according to a new study by two researchers at Princeton University.

The study, described in an article published in the June issue of Social Science Quarterly, also found that eliminating affirmative action would significantly raise the number of Asian-American students, while having little effect on white students.

If affirmative action were eliminated, the acceptance rates for black applicants would fall to 12.2 percent from 33.7 percent, while the acceptance rates for Hispanic applicants would drop to 12.9 percent from 26.8 percent, according to the study. Asian-American students would fill nearly 80 percent of the spaces not taken by black and Hispanic students, the researchers found, while the acceptance rate for white students would increase by less than 1 percent.

The researchers who conducted the study — Thomas J. Espenshade, a professor of sociology, and Chang Y. Chung, a statistical programmer at Princeton’s Office of Population Research — looked at the race, sex, SAT scores, and legacy status, among other characteristics, of more than 124,000 applicants to elite colleges.

“The most important conclusion is the negative impact on African-American and Hispanic students if affirmative-action practices were eliminated,” Mr. Espenshade said in a written statement.

Stephen H. Balch, president of the National Association of Scholars, which opposes racial preferences in admissions, said the study’s findings revealed that affirmative-action policies are “about discrimination.”

“That it’s Asian students who bear the brunt of affirmative-action policies at elite institutions strikes me as an interesting finding in and of itself,” Mr. Balch said.

As a liberal white guy who’s gone thru the elite college admissions process, I was generally okay with the idea of elite whites screwing a fraction of poor whites out of spots at the top schools. From a liberal point of view, this might be an acceptable trade-off. But what moral sense can be made of white elites screwing Asian students to pay the price of racial good-will? This should offend liberal sensibilities.

Posted by rikurzhen at 02:54 PM

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Nothing titillating for this post. Just a new PNAS paper that provides a nice example of pharmacogenetics: Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin.

David Goldstein’s group at University College London have identified genetic variations associated with dose response to two anti-epileptic drugs (AEDs): phenytoin and carbamazepine. A broad range of doses are used with these drugs, and the final “maintenance” dose for each patient is normally determined by trial and error.

In this paper, they report that a known functional polymorphism in the CYP2C9 gene is highly associated with the maximum dose of phenytoin (P = 0.0066). They also show that an intronic polymorphism in the SCN1A gene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P = 0.0051 and P = 0.014, respectively).

How does a polymorphism in an intron affect drug metabolism?

This polymorphism disrupts the consensus sequence of the 5′ splice donor site of a highly conserved alternative exon (5N), and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy.

If their findings are corroborated, genotyping could be used by doctors to more quickly determine the proper maintenance dose for these drugs.

Here are some fun parts from their discussion:

We have associated functional polymorphisms with the dose used in regular clinical practice for two leading AEDs, phenytoin and carbamazepine. For phenytoin, a well known low-activity variant in the CYP2C9 gene associates with dose, as does a functional variant in the SCN1A gene, encoding the target of phenytoin. The SCN1A variant is also highly associated with dosing of carbamazepine, thus providing functional replication of the effect of this variant. This functional replication, together with the apparent function of this polymorphism, makes a strong case that the association reported here is real. However, although the case made here is compelling, as is usual with association genetics, our results cannot be considered definitive or ready for clinical application until they are confirmed by independent replication. To our knowledge, this SCN1A variant is the first polymorphism in a drug target associated with the use of an AED and one of only a handful of target polymorphisms for which there is strong evidence of an effect on clinical drug use (22). Furthermore, our study demonstrates the pharmacologic significance of alternative splicing in a human sodium channel. Although there are other examples of alternative splicing in other human sodium channel genes, none has been associated with functional effects (23).

This polymorphism is potentially of more general importance because of the prominence of sodium channel blockade in the treatment of epilepsy (and other neurological conditions). For example, more than half of epilepsy patients treated pharmacologically in the United Kingdom receive a drug that principally targets the sodium channel (24).


Our results support the view that the major target, transporter, and drug metabolizing enzyme are good starting points to study drug response and that pharmacogenetic traits, therefore, are more tractable for genetic analyses than are those for common disease predisposition (22). We also emphasize that a haplotypetagging strategy (14) identified a previously unknown functional variant in the SCN1A gene. This functional variant was found 91 bp away from the nearest exon known at the time of the study, illustrating the need for exhaustive tagging.

Overall, our findings suggest that using genotype data may make it possible to safely reduce the time required to reach an effective dose. Therefore, it is also a priority to assess the utility of dose adjustment on the basis of genotype for these medicines in a prospective clinical study. Prospective studies of carbamazepine and phenytoin, informed by a detailed retrospective study, would also serve as a useful model for future pharmacogenetic studies (25).

Posted by rikurzhen at 12:06 AM

• Category: Science 
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In February we discussed a new Science paper, Whole-Genome Patterns of Common DNA Variation in Three Human Populations.

They genotyped 1.6 million SNPs in 71 unrelated individuals from three populations: 24 European Americans, 23 African Americans, and 24 Han Chinese from the Los Angeles area. While this was a tool building exercise, they did perform a number of interesting analyses on the data they collected. One that caught my eye was an analysis that looked for evidence of selection between populations. Their analysis made use of Fst calculations (a measure of how much genetic variation is between rather than within populations) for each SNP. In summary, they found that Fst was higher for SNPs in gene-containing (genic) regions than gene-poor (nongenic) regions and that Fst was higher in coding than non-coding regions. Put another way, there is greater genetic variation between the populations in the regions of the genome that are most likely to be functional. These differences were small but significant. They interpret these findings as evidence for local selection. However, when they asked the question of whether the SNPs that provided evidence for natural selection were private to a single population, they did not find this to be true. From this they conclude that most functional genetic variation is not population specific.

Any one interested in looking at this closer can find the data online here. It might be interesting to ask which genes are associated with SNPs that show high Fst.

Here is the associated text from the paper:

Evidence for natural selection between populations. It has been suggested that natural selection distorts the observed distribution of FST across the human genome and that large FST values can be used to identify candidate loci likely to have undergone local selection (13, 19). If this is true, then larger FST values should be found near functional genetic elements. We looked at the distribution of FST for SNPs that were genic or nongenic, coding or noncoding, and synonymous or nonsynonymous. We performed the analysis within subsets of SNPs grouped by MAF, so that effectively, we looked at the fraction of between-population variance for SNPs with the same total genetic variance (fig. S3). Common SNPs in genic regions do have slightly but significantly higher FST values than nongenic SNPs with the same MAF [analysis of variance (ANOVA), P = 1.8 x 10–46], and common coding SNPs have slightly higher FST values than noncoding SNPs in genic regions (ANOVA, P = 1.1 x 10–4). We did not see a significant difference in FST between synonymous and nonsynonymous coding SNPs, but our sensitivity is limited by the small sample sizes and expected correlations among SNPs within the same transcript. These results are consistent with local selection changing the distribution of FST near functional sequences. However, because the distributions of FST among genic and nongenic SNPs are very similar, large FST values by themselves appear to be very weak evidence of selection.

We performed a similar analysis to see if there is also an association between private SNPs and functional genetic elements. When conditioned on MAF, we saw no difference in frequency of private SNPs among genic and nongenic SNPs or among coding and noncoding SNPs (fig. S4). This indicates that the SNPs responsible for evidence of local selection in the FST analysis tend not to be private and instead are segregating in multiple populations. Although there are known examples linking population-specific SNP alleles to phenotypic differences (20–22), our results are more consistent with the conclusion that most functional human genetic variation is not population-specific.

Posted by rikurzhen at 12:43 AM

• Category: Science 
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This may be of interest to the SENS/lifespan extension crowd.

While discussing aging with a colleague, she mentioned that the latest theory is that DNA damage is the proximal cause of aging, and that strategies to cure aging will be limited to future genetations by this fact.

I found a good review paper (PDF reprint online) on the topic of dsDNA damage and aging. I find it fairly convincing. A quick summary:

1. Hypothesis: oxidative damage to DNA causes aging
2. All of the thus far identified premature aging syndromes in mammals involve mutations in nuclear proteins (e.g., lamin A in progeria)
3. Nonhomologous DNA end joining (NHEJ) is a major pathway for the repair of double-strand DNA breaks, but it frequently fails to restore the original DNA sequence
4. Homologous recombination (HR) is the non-destructive alternative to NHEJ
5. Gametes use HR over NHEJ (the germline is immortal); as do birds and bats compared to land mammals (with a corresponding greater lifespan)

The SENS proposal for chromosomal DNA damage only seems to address telomere shortening. Stem cell therapy is one possible work-around, but not for all tissues. I cannot imagine a good regenerative technology to address this factor in aging. Any suggestions?

Posted by rikurzhen at 09:53 PM

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No one has pointed this out yet, so I thought I would highlight a few research articles that have been published recently in the battle over race in biomedical research.

Now we have the APA (American Psychological Association) declaring that race is obsolete.

New and sophisticated methods for studying the relationship between human genetic differences, the environment, health and behavior, all made possible by the completion of the Human Genome Project, have made traditional race-based measurements of human differences obsolete, according to numerous authors writing in a special issue of the American Psychologist devoted to Genes, Race, and Psychology in the Genome Era (January, 2005).

Full text of the issue available here.

To which I would respond, then explain this:

Racial groupings match genetic profiles, Stanford study finds

Checking a box next to a racial/ethnic category gives several pieces of information about people – the continent where their ancestors were born, the possible color of their skin and perhaps something about their risk of different diseases. But a new study by researchers at the Stanford University School of Medicine finds that the checked box also says something about a person’s genetic background. . . .

The people in this research were all part of a study on the genetics of hypertension, recruited at 15 locations within the United States and in Taiwan. This broad distribution is important because it means that the results are representative of racial/ethnic groups throughout the United States rather than a small region that might not reflect the population nationwide.

For each person in the study, the researchers examined 326 DNA regions that tend to vary between people. These regions are not necessarily within genes, but are simply genetic signposts on chromosomes that come in a variety of different forms at the same location.

Without knowing how the participants had identified themselves, Risch and his team ran the results through a computer program that grouped individuals according to patterns of the 326 signposts. This analysis could have resulted in any number of different clusters, but only four clear groups turned up. And in each case the individuals within those clusters all fell within the same self-identified racial group.

“This shows that people’s self-identified race/ethnicity is a nearly perfect indicator of their genetic background,” Risch said.

And this:

Hypertension in African Americans linked to two genomic regions

A first-of-its-kind application of a novel statistical method of analysis to African Americans has identified regions on chromosomes 6 and 21 that likely harbor genes contributing to high blood pressure in that group. The novel statistical method, called admixture mapping, narrowed the search for genes related to hypertension, bringing researchers and doctors closer to finding more effective treatments. . . .

In the U.S., 65 million people have high blood pressure, but it is found more often in African Americans than other groups. African Americans suffer from earlier and more severe hypertension and have a higher rate of death from stroke, heart disease, and kidney failure as a result.

The causes of hypertension are complex. Diet, exercise and stress contribute, but so do genetic factors. . . .

In a fresh approach to the problem, the researchers applied a genome-wide scan that compared how often genetic variations occur in people of African or European descent to how often they occur in African Americans.

As a group, African Americans can trace their ancestry largely to populations from both Africa and Europe. “The statistical technique we used is ideal for groups who have a trait with a higher occurrence–such as hypertension in African Americans–and who stem from two sets of ancestral populations that have differing genetic variations,” Rao says.

“The admixture mapping method has distinct advantages over other more commonly used methods for population analysis,” says C. Charles Gu, Ph.D., assistant professor of biostatistics and a co-author of the report. “We looked for genomic regions with an ‘excess of ancestry’ from one of the two populations. In this case we looked for excess ancestry from the African population, because it has a higher frequency of genes contributing to high blood pressure.” Excess of ancestry is a term indicating the genomic region in African Americans is derived more often from one ancestral population than the other.

The researchers looked at the distribution of 269 genetic markers across the genome in each of the three groups. Compared to African Americans without high blood pressure, African Americans with high blood pressure were more likely to have a distribution of markers–in the identified genomic regions–resembling that of the African (ancestral) group.

The excess African ancestry among people with high blood pressure enabled the researchers to find two locations, one on chromosome 6 and one on chromosome 21, that stood out with the strongest association to high blood pressure in African Americans. Other markers close by on the same chromosomes also had a strong association with high blood pressure, indicating that the chromosome regions near these two groups of markers probably contain genes responsible for an increased risk of hypertension.

Researchers can now use this information to help locate genes affecting hypertension. “When a specific gene variant associated with hypertension is identified, physicians will be able to test patients for their risk of hypertension to head it off early,” Rao says. “In addition, research institutions and pharmaceutical companies can develop new drugs that compensate for the effect of that gene.”


Tang H, Quertermous T, Rodriguez B, Kardia SL, Zhu X, Brown A, Pankow JS, Province MA, Hunt SC, Boerwinkle E, Schork NJ, Risch NJ. Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies. Am J Hum Genet. 2005 Feb;76(2):268-75. Epub 2004 Dec 29. PMID: 15625622

Zhu X, Luke A, Cooper RS, Quertermous T, Hanis C, Mosley T, Gu CC, Tang H, Rao DC, Risch N, Weder A. Admixture mapping for hypertension loci with genome-scan markers. Nat Genet. 2005 Feb;37(2):177-81. Epub 2005 Jan 23. PMID: 15665825

Addendum from Razib: PDF of the Risch paper in question.

Posted by rikurzhen at 05:10 PM

• Category: Science 
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I just noticed this new blog: RealClimate. It appears to be the Gene Expression of climate research.

Posted by rikurzhen at 09:00 PM

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I noticed a new paper today (“Differential Distribution of Allelic Variants in Cytokine Genes among African Americans and White Americans”).

From the press release:

“We found that African Americans were significantly more likely to carry genetic variants known to stimulate the inflammatory response,” … “At the same time, genotypes known to dampen the release of anti-inflammatory proteins were more common among African Americans. This is kind of a double whammy.”

Their method:

Specifically, scientists compared genetic data on 179 African-American and 396 white women who sought prenatal care and delivered uncomplicated, single, first births at Magee-Womens Hospital of the University of Pittsburgh Medical Center between 1997 and 2001. Blood samples were analyzed for a multitude of functionally relevant allelic variants in cytokine-regulating genes.

And an unexpectedly candid result:

“In the past, people looked at one or two variants,” said Dr. Ness. “We looked at a whole host, and saw trends that perhaps point to some evolutionary-mediated change in the human genome that has had an impact on inflammation.” Posted by rikurzhen at 12:30 PM

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Reason magazine has a new article making the case for open borders. You can join the discussion here.

Posted by rikurzhen at 04:31 PM

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via [email protected]: A new PNAS paper describes a successful attempt to engineer behavior with gene therapy in primates. (GNXP mirrored full PDF). The temporary effect:

Like many humans, monkeys tend to slack off when their goal is distant, then work harder as a deadline looms. But when a key gene is turned off, the primates work hard from the word go, researchers report in PNAS Online1.

“The gene knockdown triggered a remarkable transformation in the simian work ethic,” says Barry Richmond of the National Institute of Mental Health in Bethesda, Maryland, who studied the animals.

With the gene turned off, the monkeys were unable to anticipate how many trials were left before the reward was given. They stopped procrastinating and worked hard throughout the task, making consistently fewer errors at every stage. The monkeys became extreme workaholics … This was conspicuously out-of-character for these animals.

Beyond the cool factor, this technique could be applied widely to associate genes with cognitive functions.

Godless comments:

First, I think this paper should have gone to Science/Nature/Cell. It’s that good. Some of the more interesting aspects:

Their use of antisense DNA (not RNAi) means that this method is generalizable – any neural genes whose expression you wish to reduce can be potentially affected even if all you have is the base pair sequence. While this has been worked on for some time (as far back as 1998), this is probably the most spectacular example to date. (I’m open to corrections from someone more familiar with the neuropharmacology literature.)

What’s so cool about this? Well, classical pharmacological techniques rely on the difficult, time consuming, and imprecise approach of finding compounds that will bind to a desired gene product (often by trying out chemical analogs of known interacting proteins). This requires lots of experiments; though guys like Stuart Schreiber at Harvard are working on high-throughput screening methods for chemical genomics, rapidly finding specific and consistent small molecular agonists of particular gene products is still an open problem.

Antisense-based pharmacology is a major advance as it throws open the doors to immediate, precise, “digital” gene knockdown. All you need is the base-pair sequence of the gene to get a potentially surgical, targeted antigene agent.

This may have implications for the momentum towards more use of RNAi and antisense based drugs – something I’ve heard about but haven’t done much reading on. But see here.
On a less technical note, it’s clear that this sort of thing could be done with humans. The obstacles to studying human cognition in this fashion are ethical – not technical.

Here’s the full PDF, from lead author Zheng Liu. Most interesting clips:

When schedules of several operant trials must be successfully completed to obtain a reward, monkeys quickly learn to adjust their behavioral performance by using visual cues that signal how many trials have been completed and how many remain in the current schedule. Bilateral rhinal (perirhinal and entorhinal) cortex ablations irreversibly prevent this learning. Here, we apply a recombinant DNA technique to investigate the role of dopamine D2 receptor in rhinal cortex for this type of learning…

These results suggest that the D2 receptor in primate rhinal cortex is essential for learning to relate the visual cues to the schedules. The specificity of the receptor manipulation reported here suggests that this approach could be generalized in this or other brain pathways to relate molecular mechanisms to cognitive functions…

Monkeys, as do humans, quickly learn to use visual cues to adjust their behavior based on how much work has been completed and how much remains (the relative workload) before reaching a goal or obtaining a reward (1–4). Because of its strong inputs from the ventral visual pathway and projections to the hippocampal formation (5–13), the rhinal (perirhinal and entorhinal) cortex has been heavily investigated for its role in visual recognition memory (14) and acquisition of stimulus–stimulus associations (15–18). In addition, we became interested in its role in reward-related learning because of its dense innervation by dopamine-rich fibers (19–22), which presumably arise in the substantia nigra pars compactaventral tegmental area complex (23). Using a behavioral task, visually cued reward schedules, in which the monkeys are required to perform multiple operant trials to obtain a reward at the end of a schedule, we previously demonstrated that bilateral rhinal cortex ablations prevent monkeys from learning to use visual cues to make the behavioral adjustments in the schedule task (2) and that responses of single neurons in monkey perirhinal cortex reflect a visual cue’s relation to the progress through a schedule, i.e., relative workload (3). These latter two studies led us to conclude that monkey rhinal cortex has a critical role in establishing the associations between visual cues and this form of reward contingency…

After regaining the ability to use the cues, the behavior was stable; the relationships between theaverage error rates and schedule states were the same from the first to the third week after cues were learned…Thus, although the effect of this treatment lasts for several weeks, it is nonetheless temporary. This finding, that the ability to learn new cues recovered after treatment and proceeded at the same rate as before DNA treatment, strongly suggests that the D2 receptor targeted DNA treatment had a time-limited, reversible effect on cognitive behavior.

We have shown that direct injection of a DNA construct interfering with the function of the D2 receptor in the rhinal cortex temporarily leads to a complete inability to learn associations between visual cues and the workload remaining before reward. Thus, it appears that dopamine D2-mediated mechanisms underlie the functional role that monkey rhinal cortex plays in learning this type of association. Future studies can determine whether other types of cognitive behavior dependent on the rhinal cortex likewise depend on D2-mediated mechanisms and also clarify the precise molecular mechanism(s) by which DNA constructs interfere with behavior and receptor ligand binding. Our findings offer a strong incentive for pursuing this recombinant DNA approach as a means to interrogate and modulate the roles of specific components of the molecular pathways underlying behavior.

There are of course also possibilities for agricultural engineering: stud bulls who never get tired, horses who run till their last breath, greyhounds who “run through the line” rather than slowing down as the finish approaches.


Also see Randall Parker’s comments.

Posted by rikurzhen at 01:22 PM

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There’s a public-consumption news story at Nature describing a study that seeks to identify SNPs for human strength-training performance.

The team has already tracked down 25 genetic signposts that characterize either the muscle-bound or the scrawny group, says Hoffman. He plans to publish the results later this year.

What’s stopping this from being done with traits like IQ, which are seemingly easier to measure?

Posted by rikurzhen at 01:26 PM

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A Press release from the American Psychological Society:

SAT measures more than student performance, research shows it is also a reliable measure of IQ

Each year thousands of high school students take the Scholastic Assessment Test, or SAT, hoping to gain admission to the college of their choice. Colleges and universities use SAT scores to help project a prospective student’s performance. But research shows there is more to the SAT, that it is really an intelligence test.

Meredith C. Frey and Douglas K. Detterman, researchers at Case Western Reserve University, have shown that students’ SAT test scores correlate as highly as, and sometimes higher than, IQ tests correlate with each other. This is strong evidence that the SAT is a de facto intelligence test. Their findings will be published in the June issue of Psychological Science, a journal of the American Psychological Society.

While this finding may be surprising to many who take the test, it was no surprise to the researchers. The origins of the SAT can be traced back to intelligence tests that were originally given to screen entrants into the armed forces. Many who study intelligence had suspected that the SAT was an intelligence test though it seems no one had ever investigated the relationship.

The Case investigators studied the SAT for two reasons. First, they were looking for an easy way to obtain a measure of IQ for students who participate in their experiments on more basic cognitive processes. Giving an IQ test can take 30 to 90 minutes, and with a correlation between IQ and SAT scores, researchers now have a fairly accurate estimate of an individual’s IQ without the need to administer a lengthy test. Second, it is useful to know the relationship between the SAT and IQ so that SAT could be used as a measure of IQ in cases where patients’ IQs decline due to head injury or diseases like Alzheimer’s. It is often important to know what a person’s level of intellectual functioning was before the onset of the decline and many people have taken the SAT. According to the researchers, for those who have never taken an IQ test, the SAT could be used as a substitute.

I was under the impression that the SAT had been crippled in an attempt to diminish between group differences. Does this report seems to suggest otherwise?

Posted by rikurzhen at 03:53 PM

• Category: Science 
The major media overlooked Communist spies and Madoff’s fraud. What are they missing today?
The “war hero” candidate buried information about POWs left behind in Vietnam.
The evidence is clear — but often ignored
The unspoken statistical reality of urban crime over the last quarter century.
What Was John McCain's True Wartime Record in Vietnam?