fun with flow cytometry

I just read a very interesting paper by Tomita et al that used flow cytometry to measure the effects of hydrogen peroxide on histone acetylation.

If you're unfamiliar with flow cytometry, you should check out the excellent cytometry website at Purdue, especially their Powerpoint presentations. Short version: suspended cells are labeled with fluorescent dyes and are forced into single-file flow in a FACS (fluorescence-activated cell sorter) machine. In the machine, each cell's ability to scatter light and emit fluorescence is analyzed, allowing one to profile each cell. For example, I use flow cytometry to look at both cell size and apoptotic staining. I stain for apoptosis using Annexin V (conjugated to FITC), which binds to phosphotidylserine, a phospholipid which is translocated from the inner to the outer layer of the cell membrane during apoptosis (also during necrosis). To account for the necrotic cells, which I'm not interested, I also stain with propidium iodide, which binds DNA. Cells that are Annexin- and PI-negative are fine; cells that are Annexin-positive and PI-negative are probably in early apoptosis (the cell membrane hasn't yet ruptured, so PI can't get in), and cells that are Annexin- and PI- positive are late in apoptosis, necrotic, or dead.

I find this FACS method of detecting histone acetylation to be really interesting. Other, currently used methods of detecting histone acetylation (such as measuring release of H3) require fairly substantial numbers of cells, which can be difficult when one is working with clinical samples. Flow cytometry does not require nearly as many cells, and it has the added advantage that one can examine multiple simultaneous events in the same cell. For example, by permeabilizing the cells and staining with PI, one can examine cell cycle progression (which obviously is an important thing to study when you're looking at histones). I'd be interested in using this technique to look at changes in histone acetylation and how they affect cytotoxicity of alkylating agents (or how they effect platination). Since changes in histone acetylation can affect global chromatin structure, they can affect the vulnerability of DNA to double-strand adducts and platination. Another fun molecular-oncology use for this technique would be using it to look at tumor markers, such as promiscuously activated transcription factors, in terms of their effect on cell cycle progression (this would be especially interesting with timecourses). Oooh, and you could look at how the transcription factors affect histone acetylation, and whether histone deacetylases might be a useful treatment. Flow cytometry is a fun toy.

In other news, I found a tasty fairly cheap French place (Red Rooster Wine Bar and Cafe). Excellent, cheap food (tasty duck with pomegranate sauce!), reasonably-priced wine list (mostly French). I'm going back, and you should go too.   ¶
5:56 PM

  get your shots, please

Much has been made of a JAMA study, published July 16, which discovered an "early warning"--a rapid change in head circumference and brain size in the first year of life--for autism spectrum disorders. At the time when a child first presents with autism (2-3 years), the brain is already unusually large. The study showed that the average head circumference (and presumably brain size) of autistic children at birth was smaller than that of healthy children at birth, but that, due to two bursts of sudden and excessive growth (occuring approximately at 1-2 months and 6-14 months), autistic children end up with significantly larger brains and head circumferences than healthy children. My main reservation about this sample study is that their sample size was quite small (48 autistic children). By contrast, the study that generated the "healthy" head circumference data used in this study looked at 462 healthy infants.

Will the results of this study revolutionize the treatment of autism? In the short run, probably not. We're still pretty ignorant of the causes of autism--much work remains to be done to determine not only exactly what changes occur in the autistic brain, but why and precisely when they occur. It's that sort of research that will lead to a cure, though the JAMA study may allow earlier therapeutic intervention--both behavioral and otherwise*. However, I'm most interested in the impact this study will have on the autism/IBD/MMR theory.

For a good overview of the theory, check out the CDC's FAQs. If you're lazy, here's a brief summary: some people think that the measles/mumps/rubella (MMR) vaccine can cause intestinal abnormalities (leading to disorders like Crohns disease and irritable bowels syndrome) that lead to rapid developmental regression within a few weeks after vaccination. Since the MMR vaccine is usually given between 12-15 months and between 4-6 years, the fact that autistic children exhibit physiological abnormalities before one year of age would indicate that the changes that lead to autism occur before (and thus independently of) the vaccine.

The studies that "found" a link between the MMR vaccine and intestinal and developmental disorders were horridly problematic--small sample size, no controls, nonrepresentative samples, plain old lack of evidence, you name it (once again, check out the CDC site for a better overview). Plenty of solidly-designed studies have found no link between the MMR vaccine and autism. However, the autism/IBD/MMR theory caught the attention of the media and the general public, and it just won't go away.

The anti-vaccine faction likes to state that diagnoses of autism spectrum disorders have increased greatly in the period since the trivalent MMR vaccine was introduced in the US in 1975. While this is true, it's not exactly scientific proof that the MMR vaccine causes autism. Autism (like many other childhood mental disorders) is simply much more commonly diagnosed these days. In part, this is due to the reclassification of certain high-functioning forms of autism, such as Asperger's syndrome, under the rubric of "autism spectrum disorders". In addition, it seems like physicians are much more familiar with autism and its variants, and thus are better able to diagnose it (and to overdiagnose it).

Perhaps the anti-MMR movement represents some sort of developed-country arrogance--"oh, we have excellent sanitation and health care; we really don't need vaccines against these diseases". Newsflash--there have been recent outbreaks of measles in the UK and Germany (hardly third-world countries). Measles can cause brain damage, blindness, deafness, or even death. It's not a disease to be taken lightly.

I'm not trying to argue that we're at an ideal stage of vaccine development. The presence of thimerosal (a mercury-based preservative) in many vaccines makes me quite nervous. Also, I think it'd be interesting to see if there were any way (haplotype analysis??) to help predict whether a child might have an adverse reaction to a given vaccine. (I reckon that won't become a standard test anytime soon, but it would be a good option to have for parents who worry about vaccine safety.) Anyway, to cut the speculation short: vaccination = good. autism/MMR theory = bad and not statistically supportable. herd immunity and public health in general = your friend and mine.

*Here, I guess I'm thinking mostly of gluten/casein-free diets, but I don't know that those are supported by the soundest scientific principles themselves.
  ¶
5:20 PM

  on children's literature

Ed writes some more about Harry Potter, and in doing so references Philip Pullman (hurrah!). Pullman, for those of you not familiar with his work, is a British author of children's books whose work has won all manner of awards. In a very amusing minibio, he describes himself thusly:

Philip Pullman believes firmly in the virtues of healthy exercise and a moderate diet - for other people. It makes them feel virtuous, and makes them feel good if not happy. The most exercise he normally takes is unscrewing the top of the whisky bottle. If he liked the taste of tobacco, he would smoke vigorously. He is fond of sport, and plays it by watching television. He is a big fan of Neighbours, but that is the only soap he watches, as Neighbours gives him quite enough to think about.

Pullman is perhaps best known (by me, at least) for the trilogy His Dark Materials, which some have called the atheistic answer to the Chronicles of Narnia (I'd be more inclined to call it antitheistic than atheistic, but that's another story for another time).

To get back to my original reference, Ed discusses the dangers of writing about and for children, including that of romanticizing childhood--creating the child as a perfect, innocent, and wise superior being. Ed mentions Isaac Singer as an author who falls into this trap. Philip Pullman does not--rather, he occasionally refers to children, both in his books and in his public statements, as "ignorant little savages". Is Pullman's unromanticized view of children what makes his characters so compelling? Pullman's Lyra and Will leap off the page in comparison to, say, C.S. Lewis's Peter Pevensey, whom I always regarded as something of a sanctimonious simp.

It warms my heart to find a children's author who will argue against the innocence of youth. He's in good company, too: in our old friend, the Augfessions of Constantine, we find: "...if babies are innocent, it is not for lack of will to do harm, but for lack of strength ... But if I was born in sin and guilt was with me already when my mother conceived me, where, I ask you, Lord, where or when was I, your servant, ever innocent?" (Book I, Chapter 7). I wonder what Pullman would think to be classed with Augustine ...

Anyway, you all need to go out and read His Dark Materials now (I'll lend what volumes I have to you if I know you). Hurrah for intelligent, well-written children's literature!

  ¶
7:59 PM

  how are you doing?

Over at Crescat Sententia, Amanda Butler is resorting to German to settle the question of whether "how are you doing?" is merely a social pleasantry (to which the appropriate response is "fine, how are you doing?") or an actual question meriting an actual answer. She refers to the German greeting/response of "Wie gehts?"/"Es geht" ("How goes it?" "It goes."), which allows a response which is both socially acceptable and truthful.

I was curious to see how the situation was handled in French, so I dragged out an old grammar. In French, one may answer the question "Ca va?" (literally, "It goes?") with several answers, including "ca va" ("it goes"), "ca va bien" ("it goes well"), "ca va mal" ("it goes badly"), "ca ne va pas" ("it doesn't go", translated by my grammar as "things aren't going well"), "pas mal" ("not bad"), and "comme ci, comme ca" ("so-so"). It would appear, then, that there is no one socially mandated response to "ca va".

So the French question has no single correct answer, the German question has only one, and the American question is debatable. How does this problem work in other languages? Spanish? Russian? Please tell me if you know.   ¶
6:19 PM

  wouldn't RNAifan make an awesome movie?

A n article in Friday's Chicago Tribune refers charmingly to the "legions of fans" of RNA interference (RNAi). I don't really recommend the article, as most of the information in it is, at best, misleadingly presented and rather dumbed-down. However, RNAi is a really interesting technique, and I think more people should know about it.

Essentially, RNAi relies upon a cellular phenomenon in which the presence of short sequences of double-stranded RNA (dsRNA) causes the cell to destroy all copies of single-stranded RNA (ssRNA) with the same sequence. Researchers use dsRNA sequences that are unique to a specific gene to cause only that gene's mRNA to be destroyed. This results in a null phenotype (if no gene product can be made) or a hypomorphic one (if not all the RNA is destroyed). In addition to destroying ssRNA, RNAi can lead to global silencing of the target gene, an effect that has been observed in nematodes.

RNAi is a powerful tool for deciphering gene function. For example, the genome of the nematode C. elegans has been sequenced, but the functions of all its genes are not yet known. By feeding C. elegans bacteria that are genetically engineered to express certain dsRNAs, researchers can use RNAi to examine gene function by looking at knockouts. RNAi is not yet optimized for use in mammals (more on that later), but when or if it is, it will make the creation of knockout animals much easier. At present, it takes about six months to engineer a knockout mouse. If the gene that's being knocked out is important in development, researchers must develop conditional knockouts (in which the animal is allowed to develop before the gene is turned off using retroviral proteins such as Cre), which are even more difficult. RNAi presents the possibility of creating knockout mice quickly and reliably. Aside from the obvious advantage of expediting research, RNAi could make mouse work significantly cheaper (the cost of maintaining mice can be prohibitive).

As I'm sure you know, people only really get excited about novel techniques if there's big money involved. Happily for RNAi's aforementioned legions of fans, there is. Drug companies are very excited by RNAi for two reasons: RNAi-developed knockouts may be useful for elucidating signalling pathways and providing drug targets, and RNAi itself may be used as a therapy in some human disorders and infectious diseases, such as AIDS and hepatitis C.

There are, of course, plenty of difficulties with RNAi that have yet to be completely resolved. Firstly, there are the problems common to all drugs, like potency and bioavailability. RNAi appears to be both more potent and more able to get into tissues than previous RNA-based experimental therapies such as ribozymes or antisense oligonucleotides. However, RNAi potency appears to be strongly sequence-dependent. A single mismatch in the middle of the sequence can severely diminish activity (mismatches on the end are better tolerated), and two mismatches are likely to abolish activity. This poses a serious problem for using RNAi against cancer and viral diseases, as both cancers and viruses are highly mutable. As far as bioavailability goes, it seems there's a bit of a debate going on (detailed in a Compugen article. No one seems to like using vectors to deliver dsRNA--given the very public failure of several recent vector-based gene-therapy attempts, this is understandable. Some firms, such as Ribopharma, favor delivering naked, unmodified dsRNA to patients, whereas others, such as atugen and Ribozyme, prefer to deliver chemically stable forms of dsRNA to increase the half-life.

Another important problem in using RNAi as a therapeutic agent is the exquisitely complicated mammalian antiviral response. In humans, long dsRNA (greater than 30bp) triggers a two-pronged cellular response: in one pathway, the protein kinase PKR is activated, leading to a downstream interferon response. In another, RNase L, which degrades all RNA, is activated. Because of this dsRNA-dependent response, short interfering RNA (siRNA), usually about 19-21bp long, is the method of choice for mammalian therapeutics. However, there may still be minor PKR pathway activation even with siRNA.

The bottom line: no, RNAi may not live up to the hype. The sequence specificity required for potency may prove an insurmountable problem, and it seems unlikely (unless there's some huge new development in pharmacogenetics) that RNAi will ever be useful as a standard therapy. However, as we move into an age of personalized medicine (okay, as I hope we're moving that way), RNAi may present a uniquely effective tool in some otherwise untreatable diseases. We'll have to wait and see.
  ¶
4:41 PM

  pharmacogenetics in the news!

An interesting NYT article, as well as a Yahoo! Business article concerns a genetic test, the AmpliChip CYP450, that's supposed to be the latest thing in "personalized medicine" (which, so far as I can understand it, is laymanese for pharmacogenetics). The test, produced by Roche, is an Affymetrix chip that can be used to probe for polymorphisms in two CYP450 family proteins (CYP2D6 and CYP2C19, if you're curious). These proteins are involved in the metabolism of about 20-25% of all commonly prescribed drugs; I'm told that CYP450-family proteins are involved in the metabolism of about 60% of drugs. Presumably, the test will identify patients with faulty CYP2D6 and CYP2C19 enzymes who should avoid taking high doses of drugs metabolized by these enzymes. The idea, of course, is very cool. The fact that they tried to do a strange little end-around to get by FDA inspections is somewhat less cool (and is detailed in the NYT article).

I have a few questions about the chip.

Are they probing the entire gene? When one hears about Affymetrix chips (and other microarray techniques) in basic research, usually what's done is that the researcher collects RNA pools, reverse-transcribes them, amplifies and labels them and probes with the resulting labeled cDNA. However, using cDNA to probe for polymorphisms might not be ideal; for example, some polymorphisms are intra-intronic and affect the gene product only by interfering with splicing or RNA stability.

Will this technique catch only missense or nonsense mutations, or will it catch noncoding mutations as well? Noncoding mutations are mutations in which the amino acid of the gene product isn't changed, as in a UCU->UCC mutation--the amino acid signified by both of these codons is serine, so this mutation does not affect the protein. However, it would show up as a polymorphism in the gene (or in the cDNA), and this patient would be identified as possessing a faulty enzyme. I think that this is likely to be a problem with this test, and its effects--patients taking insufficient medicine, or less potent medicine than is available--are to be avoided. Does Roche have a plan to address this failing?

Finally, does the test probe for specific polymorphisms, or does it just show if the patient's gene does not match the "correct" sequence? If it probes for specific polymorphisms, are we sure that we know all possible polymorphisms for these genes?

  ¶
5:05 PM

  baddest public transport in the whole damn town

It seems that the CTA and I are in agreement: the South Side needs el service.
  ¶
4:15 PM

  hello again

Getting cable (ooh, exciting) and getting my hair done (ooh, four hours of my life I want back) have been eating up my time lately. Just a few things ...

I am suggestible.
As soon as the cable guy left, I started checking out the cable. I landed on the Food Network. Fifteen minutes later, I was at the Co-op. I ended up making chicken adobo and some sort of vaguely Roman (white wine, garlic, pepper) attempt at broccoli.

other people you should read
Paul of KIPlog thinks that this is an excellent blog (I'm flattered). Check out his blog, which itself is excellent and contains truly exhaustive topical lists of other blogs.

Charles Murtaugh has an excellent entry on cancer models that you should read.

read the damn label!
Yesterday's Trib had an irritating article on the Pill that seemed to imply that doctors had been hiding some of the Pill's side effects (loss of libido and sexual dysfunction) from their patient. PUBLIC SERVICE ANNOUNCEMENT: if you are taking any sort of medication, it behooves you to know what it can do to you. Read the label, talk to your doctor, call the company, whatever it takes--know what you're putting into your body. And hey, maybe you could support proper sex education so that your kids will be better informed about their sexual health than you are. Just a thought. Which brings me to ...

ask a biologist
I've been getting a LOT of google hits about birth control lately. What little information I do have up on birth control seems inadequate to answer many of these questions. Therefore, I invite you to email me with your questions, which I will do my best to answer. Questions not concerning birth control are fine, too.   ¶
5:32 PM

  hurrah for bill gates

Today's Washington Post includes an article about the Gates Foundation's work towards funding immunization research. It seems he's providing a great deal of the funding for the Global Alliance for Vaccines and Immunization (GAVI), an organization that's working with drug companies, public health experts, and economists, among others, to create a "stronger global procurement system" for vaccines. As things stand, there's no way a drug company would create a vaccine for a pathogen like malaria--there is absolutely no profit in such a project, and big pharma is only interested in profitable research.

Given the possibility that I may work in industrial pharmacology, I'm quite curious about GAVI. It seems that in recent years, the U.S. government has exercised much more influence over the pharmaceutical industry. The prime example I can point to is the Orphan Drug Act (1983), which provides grant funds and tax credits for clinical testing for drugs and other treatments meant to treat rare disorders (disorders affecting less than 200,000 people in the U.S.). The ODA also guarantees the developers of orphan drugs seven years of exclusive marketing privileges. (Japan has had a similar system in place for years, and the EU is developing one.) One of the biggest ODA success stories has been Gleevec, an extremely potent "smart drug" used to treat chronic myelogenous leukemia (CML)patients who have the BCR/ABL translocation. Each year, 4500 Americans are diagnosed with CML, and 2400 of them die of their disease--obviously, this definitely qualifies as a rare disorder. A list of other ODA-funded drugs can be found here. As one might expect, the ODA has drawn criticism for allegedly granting companies monopolies on potentially life-saving drugs (though one can counter that, without the ODA, the drugs probably wouldn't exist). There have also been some unusual cases such as that of AZT, which was approved in 1989 as an orphan drug to treat full-blown AIDS (at that time, a disease suffered by about 45,000 Americans) but later was found to be effective in delaying the onset of AIDS, making it useful to about 600,000 HIV-positive Americans. Obviously, there are some bugs to be worked out. (I recall reading that the EU's plan included a proviso that would shorten the duration of marketing exclusivity should the patient pool be found to be larger than was previously surmised, which would be a big improvement.)

Given the relative success of the ODA, it's interesting to think about the possibility of some sort of publicly funded version of the Global Alliance for Vaccines and Immunization (rather like the IMF, only with drugs). In a sense, funding vaccination programs for underdeveloped countries would be easier than funding drugs--many deadly childhood diseases, like measles, already have vaccines developed, so it would be more of a problem of distribution. Additionally, many pathogens, like rotavirus*, should be relatively easy to vaccinate against--however, since rotavirus isn't a major cause of death in America, there's never been a reason for anyone to make a vaccine. It's awfully tempting to contemplate such a venture as a way to wipe out more diseases (well, diseases without animal hosts, at least). And this global vaccination organization could be an excellent central organization to mobilize treatment for pandemics (aren't we due for a new flu sometime soon?).

If nothing else, such an organization would draw some awesome protestors--anti-globalization plus anti-big pharma plus anti-vaccines--what fun!


*Rotavirus--a small, ssRNA virus that can cause severe diarrhea in children. About 5% of all deaths of children under five are due to rotavirus infection (of course, rotavirus kills many more children in undeveloped nations than in developed ones). Thank you, Viruses of Eukaryotes.   ¶
3:43 PM

  de-uglification project
Playing around with a new (and less screamingly purple) template. Let me know if anything goes horridly wrong.  ¶
5:50 PM

  power in numbers
As you've probably heard, U.S. News and World Report has dropped the "yield rate" (the percentage of students admitted to a school that accept their admission offer) from its oh-so-influential college rankings. Since the yield rate accounted for about two percent of a school's score, this isn't expected to create a huge difference in the rankings; rather, it seems to be more of a symbolic move that distances U.S. News from the much-debated practice of binding early-admission programs (which increase the yield rate). Acceptance rates for early-admission programs tend to be higher compared to regular admission, which encourages students--particularly wealthy students who will not need to compare financial-aid packages from different schools--to use them for competitive universities. If you're not familiar with these programs and their criticisms, I refer you to an excellent (though California-school-biased) article in the Atlantic Monthly.

Honestly, I think the U.S. News rankings are pretty pointless, and it irritates me that people take them as seriously as they do. (Part of this is sour grapes--in this year's rankings, Northwestern is ranked ahead of the University of Chicago. I realize that I'm biased, but come on--that's just ridiculous.) I don't know if it's possible to come up with a good, useful system for ranking universities, nor do I know if such a system is needed--if we didn't have one, perhaps students would have to independently find colleges that fit them well, rather than shooting for a big name. The U.S. News rankings may be as close as we can reasonably come to a good ranking, but I'd still like try and poke some holes in it. Therefore, a look at their criteria:

NB: U.S. News and World Report does not seem to tell (on its webpage, at least) how it ranks its criteria, so I've pulled some rankings from an interview in the NYT article linked above. If you can find any more, please let me know.

Peer assessment (25% of total score): "Top academics"--presidents, provosts, and deans of admission--rate other schools' academic programs. I like this criterion very well; as U.S. News says, it allows the survey to account for intangible factors (such as faculty dedication to teaching) that can have a great influence on students.

Retention and graduation rates (together, 20%): The retention ranking encompasses both the six-year graduation rate (80%) and the freshman retention rate (20%). I hate it. First of all, it rewards schools like Princeton, which accept a fairly small percentage of applicants but don't work them very hard once they're in. Secondly, not everyone leaves because of the school. Of the people I've known who've left the university, the overwhelming majority left because of financial or health-related problems (while one could argue that the University of Chicago can be fairly abusive to one's financial and mental health, I can't claim that the school was wholly to blame in any of these cases). The graduation rate measures the actual graduation rate from the university against a "predicted" one generated using (among other factors) expenditure per student and standardized test scores. I think this is a neat idea, but I really hate that they use SAT scores, which provide little information about how well a student will perform in college.

Faculty resources (20%): Another one I don't mind. This encompasses class size, salary, percentage of faculty with the highest degree in their field, percentage of faculty who are full-time, and student-faculty ratio. Happy, committed, brilliant, accessible faculty make happy, smart students.

Student selectivity (15%): This is the category that formerly included the yield rate (which counted for about 10% of the score in this category). They also count in SAT/ACT scores (yuck), students who graduated in the top 10% of their high school class (this hurts students from competitive high schools), and the rate of students who apply to students who are accepted. As a University of Chicago student, I think I'm required to start bitching about how we have a self-selecting applicant pool, so this ranking hurts us unfairly. As you can probably tell, I don't like this ranking.

Financial resources (some percentage of the remaining 20%): On the principle that more money spent per student equals more programs and opportunities for the student, this criterion rates per-student spending. I can't argue with rating this, but I'm certainly glad that faculty resources count for more.

Alumni giving rate (the rest of the 20%): It looks like they consider the two financial years right before the data collection. I wonder how much schools that place a lot of applicants in graduate or professional schools right after graduation are hurt by this. Does the presumable increased amount of giving ten or fifteen years down the line make up for the fact that students will be unable to give much while they're continuing their education?

A few ideas for other criteria to consider: I wish U.S. News and World Report would take graduate and professional school (and, of course, job) placement into account in these ratings. While it might be difficult to get this information from the universities (since it may be hard for them to find out what their students end up doing), it might be possible to get the perspective of grad/med/law/business school deans of admission (and corporate hiring directors) through surveys. I'd also like to see some consideration of how much emotional support the school provides for each student (I realize that I'm getting into hard-to-quantify territory here, and that this is sort of lumped in under financial resources). It'd be hard to rank, but one might look at how many support people (advisers, RAs, etc.) the student has access to, the number of students each support person serves, and the availability of free or cheap therapy (I wonder if this is the sort of thing you'd only worry about if you went to Chicago).

I'd love to know what other people think about these ratings.  ¶
5:07 PM

  love in the time of ... college
Ages and ages ago, I said that I'd offer a defense of the one-night stand. In thinking about this, and in reading an essay by Miss Manners cited by Will (you know, if I'm going to link to you people every single time I post, it might be time to put you on the sidebar), I began to conceive the true bizarreness of the world of collegiate romance.

There's a joke, or perhaps a traditional belief, at the University of Chicago that seventy-five percent of students who date each other for a year or more will marry. I once knew a math concentrator (now married to another Chicago student) who wrote an algorithm that predicted the likelihood of marriage based on relationship length (from what I'm told, it was fairly accurate). There's a fairly common perception that relationships at Chicago--and to some extent, at college campuses in general--fall into two groups: hypercommitted (which encompasses many of the aforementioned directly premarital relationships, as well as serial
monogamy) and hypocommitted (one-night stands or "the hookup culture"). Some people point to coed dorms as the cause, which I don't think I buy; while living with the other gender certainly can facilitate both relationship extrema, I find it hard to see it as the cause. But what's to blame? Is the high rate of divorce causing some sort of mixed mania of and phobia for committment? Is it just slust*?

I want to know what you think.

*Ah, slust (i.e. sloth plus lust). Is it a uchicago coinage, or is it more widely used than that?
  ¶
5:26 PM

  briefly
Talk of Freudian analysis and Harry Potter on Crescat Sententia (as well as the near-constant talk of Harry Potter on Mildly Malevolent) reminded me of an LRB article by the redoubtable Wendy Doniger on Harry Potter and the Family Romance (which is not the title of book six). The article's no longer up on the LRB's website, but an edited version exists on Fathom.com.

Ed brings up the inscrutable Howard Dean, and has more intelligent things to say about him than I will. I'd be interested to hear what he has to say about universal health care (and what role, if any, this issue will play in his campaign). What little campaign literature I've seen has featured it quite prominently, but I haven't really read that much about it in the media. I was amused to note that the campaign volunteers were handing the aforementioned literature out at the farmers' market in Naperville--didn't really seem like the right crowd.

While I'm speaking about health care, I should mention that all insurers in Illinois (well, all that cover prescriptions) must now cover all FDA-approved birth control drugs and devices. Full story's in the Chicago Tribune (free registration required). Hurrah! Only took, uh, forty years.

On a lighter note, it has come to my attention that the Pub now has trivia nights on Tuesdays. Does anyone want to go?  ¶
5:24 PM

  a place for everything
Because it pains me terribly to have things post out of order, here's an ordered list of the birth control posts.

(1)
(2)
(3)
(4)
(5)
(6)
(7)

More later on the dearth of research for new contraceptives and why it really wouldn't be so hard to do said research.

And no, Amanda, I haven't forgotten about the defense of the one-night stand. Well, actually, I sort of had, but now I remember. :)

p.s. I can only imagine what my search hits will soon look like. And my banner ads.   ¶
5:00 PM

  men:


condom


definition: A sheath that fits over the erect penis. Usually made of latex, but can be made of other materials (lambskin, plastic, etc.).

cost: About twenty cents to $2.50 per condom, though family planning centers and colleges may give them away. Lubricated condoms average
about $6 per dozen. Animal tissue or plastic condoms are more expensive (around $25 per dozen).

availability: readily available.

positive side effects: may prolong erection and prevent premature ejaculation.

negative side effects: dulls sensation.

% efficacy: with typical use, 86%. with perfect use, 98% (according to Planned Parenthood). More effective when used with spermicide (such as nonoxynol-9).

protection against STDs: Latex condoms provide the best defense against STDs of all forms of birth control methods. Animal skin condoms are thought to be permeable to viruses such as HIV and hepatitis B, and there's not enough data available on plastic condoms to determine their protective effect against STDs.

convenience: Cheap, easy to acquire, don't require a prescription.

notes: As might be obvious, people with latex allergies shouldn't use latex condoms. Also, latex can deteriorate, so condoms should not be exposed to high temperatures nor kept longer than a few years.


vasectomy


definition: The vas deferens (tubes that carry sperm to the penis) are severed and sealed (with clips or sutures). Vasectomy is usually an outpatient surgery.
cost: $250-$1000.

availability: Must be done in a clinic or a doctor's office.

positive side effects: None.

negative side effects: The severed ends may develop nodules, which can become infected. There appear to be no long-term health risks associated with vasectomy.

% efficacy: The Mayo clinic gives the failure rate as less than 1%. The major cause of failure is waiting long enough after surgery to have unprotected sex (normal wait time is about three months). Rarely, the severed ends of the vas deferens may rejoin and cause failure.

protection against STDs: None.

convenience: Same as tubal ligation--once the procedure is done, protection should be permanent.

  ¶
3:35 PM

  women, permanent method:

permanent methods:


tubal ligation


definition: A surgical procedure in which the fallopian tubes are sealed (by clips, electrocoagulation, or removal of parts of the tubes). Usually performed as day surgery.

cost: $1000-$2500.

availability: Must be performed at a hospital or clinic surgical unit.

positive side effects: Possible slight protection against ovarian cancer and PID.

negative side effects: Increased risk of ectopic pregnancy, should pregnancy occur. According to the Mayo Clinic, "The long-term effects of tubal ligation on the menstrual cycle, pelvic pain and later pelvic surgery are controversial." (Studies show little difference in menstrual cycles before and after sterilization.) In addition, there are the general risks associated with any type of surgery.

% efficacy: The Mayo Clinic cites the 10-year failure rate as 2%.

protection against STDs: Little to none, except for the aforementioned protection against PID.

convenience: Once the initial operation is completed, you don't have to think about protection (against pregnancy ONLY) again.

notes: Tubal ligation is theoretically (though not always practically) reversible.

  ¶
3:34 PM

  women, hormonal methods (ctd.):

Ortho-Evra ("the patch")


definition: A thin plastic patch which is attached to the buttocks, stomach, upper outer arm, or upper torso. The patch is applied once weekly for three weeks; no patch is used in the fourth week. The patch secretes synthetic progestin and estrogen. These hormones prevent ovulation; additionally, they may increase the thickness of the cervical mucus or prevent implantation of a fertilized egg.

cost: The cost of the inital physician's visit ranges from $35-$125. Ortho-Evra itself costs between $30 and $35 per month ($360-$420 per year).

availability: prescription only.

positive side effects: regular, lighter, shorter periods. Though long-term studies are not available, it is expected that Ortho-Evra will have similar long-term use side effects as the pill.

negative side effects: bleeding between periods, weight gain or loss, sore breasts, nausea, mood swings. Other side effects include skin reaction
to the patch itself and difficulty in wearing contact lenses. Slightly increased risk of liver tumors or blood clots--these risks can be exacerbated in women over 35, women who smoke more than 15 cigarettes per day, women with blood clotting disorders, or women already at greater risk for heart disease. Rare side effects include high blood pressure and jaundice.

% efficacy: With perfect use, greater than 99%. Not enough studies have been performed to determine the success rate with typical use, but it's
estimated to be better than that of the pill, so greater than 92%.

protection against STDs: none.

convenience: Must remember to change patches on the same day of every week.

notes: Antiseizure medications and certain antibiotics (rifampin) make Ortho-Evra less effective. In addition to the normal contraindictions for hormonal birth control (see Norplant or Depo-Provera), Ortho-Evra is contraindicted in women who get migraine headaches, who weigh more than 200 pounds, or who have ever experienced jaundice due to pregnancy or birth control.


NuvaRing ("the ring")


definition: A small, flexible ring that is inserted into the vagina once a month for three weeks. It releases synthetic estrogen and progestin. For an explanation of NuvaRing's contraceptive effect, see the definition for Ortho-Evra.

cost: The cost of the inital physician's visit ranges from $35-$125. NuvaRing itself costs between $30 and $35 per month ($360-$420 per year).

availability: prescription only.

positive side effects: regular, lighter, shorter periods. Other positive noncontraceptive side effects are expected to be similar to those of the pill.

negative side effects: bleeding between periods, weight gain or loss, nausea, sore breasts, mood swings. Also, increased vaginal discharged or irritation of the vagina may occur. Slightly increased risk of liver tumors or blood clots--these risks can be exacerbated in women over 35, women who smoke more than 15 cigarettes per day, women with blood clotting disorders, or women already at greater risk for heart disease. Rare side effects include high blood pressure and jaundice.

% efficacy: As with Ortho-Evra, there are insufficient studies to determine the success rate of NuvaRing with typical use. However, with perfect use,
NuvaRing is greater than 99% effective, and it is expected to be greater than 92% effective with typical use.

protection against STDs: none.

convenience: Fairly simple to use, but you must be careful to remove it and replace it at the proper times.

notes: NuvaRing is light and heat sensitive and must be stored away from direct sunlight and high temperatures. Antiseizure medications and antibiotics like rifampin may decrease the effectiveness of NuvaRing. May fall out--must be replaced within three hours. You should not use the ring if you have weak pelvic floor muscles or if you suffer from chronic constipation.
  ¶
3:32 PM

  women, hormonal methods:

oral contraceptives ("the pill")

definition: Packs of 28 pills, taken daily, which contain synthetic estrogens and progestins. Like other combined-hormone methods, the pill works primarily by preventing ovulation and secondarily by thickening the cervical mucus and preventing implantation.

cost: $15-$35 per month, though you can get them more cheaply at clinics. Also, a physician visit ($35-$125) will be necessary to get the prescription.

availability: Prescription only.

positive side effects: Decreased risk of ectopic pregnancy, should pregnancy occur. Regular, shorter periods, which can prevent menstruation-associated anemia. Some women experience a reduction in acne, abnormal hair growth, and menstrual cramps. Decreased risk of endometrial and ovarian cancer, pelvic inflammatory disease, benign breast growths, and ovarian cysts. Better bone retention (like hormone therapy).

negative side effects: Use of oral contraceptives is associated with an increased risk of heart attack, stroke, and blood clots. This risk is increased by cigarette use. Less serious side effects include nausea, acne, abnormal hair growth, weight gain, sore breasts, moodiness, depression (or increased depression), dizziness, decreased libido, and headache.

% efficacy: According to Planned Parenthood, the pill is 95% effective with typical use, though other studies say 92%.

protection against STDs: None.

convenience: You must take your pills every day at the same time for maximum efficacy. Skipping days or taking pills late may decrease your protection against pregnancy; it can also increase the unpleasant side effects.

notes: Women with clotting disorders may take a "minipill" containing only progestin. Minipills are slightly less effective and provide less protection against ectopic pregnancy. Any condition that interferes with drug ingestion (such as vomiting) or drug delivery (such as obesity) will decrease the effectiveness of the pill. Overweight women may not be able to use very low-dose pills. Antiseizure medications and antibiotics such as rifampin can decrease the effectiveness of the pill. Despite rumors, National Cancer Institute studies have shown that long-term use of the pill does not increase the risk of breast cancer. Some new oral contraceptives claim to reduce certain side effects (for example, Ortho-tricyclen is supposed to treat acne). These reduced side effects appear to be due to reduced androgenicity of the synthetic progestins in the pills. Drospirenone, desogestrel, and norgestimate are synthetic progestins commonly found in newer pills (like Yasmin and Ortho-tricyclin) that are supposed to have better side effect profiles. An interesting handout on oral contraceptives is available here.


Norplant


definition: Thin plastic implants containing levonorgestrel (a progestin) that are inserted under the skin of the upper arm. A small amount of hormone is released constantly, preventing ovulation and thickening the cervical mucus (this impedes sperm progress). It is believed that Norplant may also prevent implantation of the fertilized egg into the wall of the uterus. One insertion of Norplant protects against pregnancy for five years.

cost: Between $500-$750 (this includes a physician visit, a pregnancy test, the cost of Norplant itself, and the cost of insertion). An additional fee ($100-$200) may be charged for removal. This averages out to less than $200 per year. Financial assistance is available from the Norplant Foundation.

availability: Available only by prescription.

positive side effects: none.

negative side effects: headache, change in appetite, weight gain or loss, depression, dizziness, anxiety, sore breasts, nausea, changes in sex drive, decreased vaginal lubrication, acne, skin irritations, gain or loss of facial hair, discolored skin over the implants. Rare side effects include enlarged ovaries or ovarian cysts, increased risk of liver growths, and an increased risk of ectopic pregnancy, should pregnancy occur. Women who smoke and use Norplant have an increased risk of heart attack, stroke, and blood clots. In addition,
it is suggested that the use of Norplant may impede bone growth in young women.

% efficacy: Greater than 99.9%.

protection against STDs: none.

convenience: Aside from the minor operations required to insert and remove Norplant, it's relatively convenient--you don't have to think about birth control for five years at a time.

notes: Norplant becomes effective within 24 hours of implantation. While insertion is generally routine and painless, removal of old capsules can be difficult and may cause scarring. Norplant is contraindicted in women with a number of conditions (including survival of breast cancer or meningioma) and may be used only under careful supervision in women who suffer from several other conditions (liver disease, heart disease, diabetes, high blood pressure, and several others). Antiseizure medications and antibiotics like rifampin decrease the effectiveness of Norplant.


Depo-Provera


definition: An injection of depotmedroxyprogesterone acetate (a progesterone) into the buttock or arm that prevents pregnancy for up to twelve weeks. Primarily, it prevents ovulation; secondarily, it thickens the cervical mucus, and it may also prevent implantation of the fertilized egg.

cost: yearly costs are approximately $215-$545 (includes cost of initial physician visit, injections, and further visits). If you are more than two weeks late for your shot, you must take a pregnancy test (up to $20).

availability: prescription only.

positive side effects: lowers the risk of endometrial cancer.

negative side effects: may cause amenorrhea (observed in half of women who had used Depo-Provera for a year or more), irregular bleeding, headache, nausea, dizziness, sore breasts, weight gain, depression, hair loss, growth of facial or body hair, anxiety, skin rashes or discolorations, change in sex drive, temporary bone thinning (this does not appear to increase the risk of osteoporosis). Rare side effects include a greater risk of ectopic pregnancy, should pregnancy occur.

% efficacy: 99.7%.

protection against STDs: none.

convenience: Must keep up regular schedule of injections (every twelve weeks).

notes: It can take from twelve weeks to eighteen months following your last shot of Depo-Provera to become pregnant. Use of Depo-Provera is contraindicted in women who are taking medication for Cushing's syndrome, and requires special supervision in women who suffer from diabetes, depression, high blood pressure, blood clotting disorders, liver disease, or who have a high risk of heart disease.

  ¶
3:29 PM

  women, barrier methods (ctd.)


IUDs (intrauterine devices) (not exactly a barrier method, but hard to classify):


definition: Small flexible plastic devices containing either copper or a hormone. IUDs are inserted into the uterus by a physician. Two varieties (one copper, one hormonal) are available in the US. The copper one (Paraguard) needs to be replaced every 10 years, and the hormonal (Progestasert) one needs to be replaced yearly. It's theorized that IUDs work by affecting sperm or egg motility. In addition, the copper IUD appears to interact with uterine enzymes to prevent implantation, and it also stimulates the production of prostaglandins. The hormonal IUD secretes progestin, which thickens cervical mucus and helps prevent implantation. The IUD, which is T-shaped, has a plastic "string" that extends through the cervix and into the vagina. The string is used in the removal of the IUD, and it also helps you know if the IUD moves or becomes dislodged.

cost: The cost of the exam, insertion, and follow-up visit ranges from $250 to $450. Paraguard (good for 10 years) runs about $400; Progestasert costs
between $175 and $350.

availability: A physician visit is necessary.

positive side effects: Progestasert may cause lighter and shorter periods.

negative side effects: Cramping, backache, and vaginal bleeding after insertion. Possibility of heavier and longer periods (mainly with Paraguard), which may lead to anemia. Uterine puncture may occur (this is not actually as painful as it sounds), and the IUD may migrate in the pelvic area, requiring surgical removal. Because the insertion of the IUD may push vaginal bacteria into the uterus, women who use IUDs have an increased risk of pelvic inflammations within the first four months after insertion. There is a risk of infertility associated with IUD use. Should pregnancy occur while a woman is using an IUD, there is an increased risk of ectopic pregnancy.

% efficacy: Paraguard: 99.2% effective with typical use, 99.4% with perfect use. Progestasert: 99.7% effective with typical use, 99.8% with perfect use. To improve efficacy, additional methods of contraception (condoms, foam, etc.) should be used in the first few months. Also, the woman needs to monitor the position of the string.

protection against STDs: None.

convenience: Must be inserted by a physician, but doesn't require any sort of daily, weekly, or monthly activity to maintain contraceptive benefits.

notes: Planned Parenthood claims that IUDs are the most commonly used reversible birth control method. Really? I assume that this is because of the cost. Apparently, the IUD horror stories that one hears largely concern the Dalkon Shield (TM), which , after a famous tort case, is no longer on the market. IUDs are contraindicted in a whole bunch of circumstances, including but not limited to: bacterial STDs, any bacterial infection of the genital tract, immunosuppression or immunodeficiency, copper allergies or Wilson's disease (Paraguard only), abnormal Pap smears or uterine/cervical cancer, certain anatomical abnormalities that complicate IUD insertion and removal, and lack of access to medical care should problems develop.


Today (C) contraceptive sponge


definition: A disk-shaped polyurethane device, used with spermicide (such as nonoxynol-9). Must be inserted before intercourse. Protects for repeated acts of intercourse for about 24 hours (no reapplication of spermicide required). Must not be kept in longer than 30 hours. Sponges are disposable and should not be reused.

cost: $6 for a three-pack, $20 for a dozen.

availability: Nonprescription.

positive side effects: None.

negative side effects: Possible side effects include vaginal irritation and toxic shock syndrome (if the sponge is left in too long).
% efficacy: About 90% with perfect use and about 85% with typical use (according to manufacturer's website).

protection against STDs: None.

convenience: Very convenient to use, as it can be inserted in the morning and left in all day.

notes: Whitehall-Robins, the manufacturer of the Today contraceptive sponge, ceased production in 1994 after determining that the market for the sponge was not large enough. The Today sponge was purchased by Allendale Pharmaceuticals in 2000 and (apparently) can be purchased (from Canada) online. Like the diaphragm and the cervical cap, the sponge is not ideal for women who have given birth, as it may not fit them.

  ¶
3:23 PM

  women:


barrier methods:


diaphragm/cervical cap


definition: Both are latex barrier methods that, like condoms, prevent the sperm from encountering the egg. The diaphragm fits into the vagina and covers the cervix, while the cervical cap, which is smaller, fits directly over the cervix. Both must be used with spermicide (cream, jelly, or foam).

cost: cost of pelvic exam to be fitted (~$50-$200), cost of device (~$15-$50), and cost of spermicide ($8-17 per kit).

availability: You have to be fitted for a diaphragm or cervical cap by your healthcare provider.

positive side effects: reduce the incidence of pelvic inflammatory disease, may reduce the risk of developing cervical cancer.

negative side effects: may increase the risk of bladder infections. In rare cases, cervical hyperplasia may occur. Another rare side effect is toxic shock syndrome (TSS).

% efficacy: The diaphragm is 94% effective with perfect use (80% effective with typical use). The cervical cap is 91% effective with perfect use in women who have never given birth (80% effective with typical use). In women who have given birth, it is 80% effective with perfect use (60% effective with typical use).

protection against STDs: Cervical caps and diaphragms may provide some protection against chlamydia and gonorrhea.

convenience: They can be very difficult to insert properly (at least at first), and you have to be very comfortable with your body to use them. The diaphragm or cervical cap has to be inserted several hours before intercourse, may need a reapplication of spermicide for each additional act of intercourse (necessary with diaphragms, optional with cervical caps), and needs to remain in place for about eight hours after the last act of intercourse. The diaphragm can't be worn for longer than 24 hours (48 for the cervical cap).

notes: You may have to be refitted for a diaphragm or cervical cap after you give birth, undergo abdominal or pelvic surgery, have an abortion after 14 or more weeks of pregnancy, or gain or lose more than 10 pounds. Also, you're not supposed to use them if you have a history of TSS, a urinary tract infection, a prolapsed uterus, a bad Pap smear, or several other conditions. Also, you can't use them if you're allergic to latex or spermicide.


female condom


definition: A 6.5-inch long sheath with rings at both ends. The closed end is inserted into the vagina and fits behind the pubic bone.

cost: $2.50.

availability: While they don't require a prescription, female condoms are less widely available than regular latex condoms.

positive side effects: none.

negative side effects: none.

% efficacy: The female condom is 95% effective with perfect use (75% with typical use).

protection against STDs: Studies show that the female condom appears to be about as effective than the male condom at preventing STDs. More studies need to be done. Given the decreased protection against pregnancy versus male condoms, one would expect a similarly decreased protection against STDs. Counterintuitively, the manufacturer's website for the female condom claims that use of the female condom is associated with a 97.1% reduction in the risk of HIV per act of intercourse, while NIAID cites a review claiming that the male condom provides an 85% reduction of HIV transmission risk. The FDA claims that the female condom is less effective than the male condom in the prevention of STDs.

convenience: As convenient as the male condom.

notes: Unlike the male condom, the female condom does not require that a man maintain an erection during use. Also, the female condom is made of polyurethane, which is less likely than latex to provoke allergic reactions. The female condom and the male condom should not be used together.
  ¶
3:22 PM

  behavioral method:


natural family planning/rhythm method


definition: Abstinence during the (approximate) third of the menstrual cycle during which a woman is or may be fertile. This involves monitoring the menstrual cycle by using a calendar and by tracking changes in oral temperature and cervical mucus consistency.

cost: none (other than thermometer and calendar)

availability: n/a
positive side effects: none.

negative side effects: none (unless you count enforced abstinence).

% efficacy: With typical use, natural family planning is about 80% effective for couples. The failure rate is higher for single women.

protection against STDs: none.

convenience: It's convenient in that you don't have to run out and get a prescription, but it's not especially easy to practice.

notes: A lot of factors can interfere with monitoring the menstrual cycle. Temperature can vary due to stress, illness, sleeping patterns, alcohol intake, and a number of other things. STDs, breastfeeding, and perimenopause can alter the cervical mucus cycle. Also, the timing of the menstrual cycle can be affected by illness, anxiety, and any number of other things (plus, it's generally fairly irregular in younger women). FWIW, natural family planning is the only method of birth control approved by the Catholic Church.

  ¶
3:21 PM

  This birth-control thing has taken me an embarrassingly long time to write. With any luck I'll be able to put it up soon.   ¶
2:33 PM

  I've moved, and my place is fabulous. You have to come visit.

I'm not feeling quite as literate as Ed or Kathleen at the moment, but I have been reading a very entertaining group biography of the Mitford sisters (The Sisters, ). The six Mitford sisters, if you're not British and under 50 (according to the author, you must meet these criteria to know who the Mitford sisters are), were the children of minor aristocrats who led very adventurous lives--Unity was a friend of Hitler and shot herself when England declared war on Germany, Decca was an outspoken communist, and Diana got Evelyn Waugh all hot and bothered. So far, it's great fun.

Oh, and HAPPY TWENTY-FIRST BIRTHDAY, KATHLEEN!!!!!!!!!!!!!!!   ¶
6:37 PM