Instead of a tough-talking mayor, new windows may be to thank for the drop in violent crime in New York City. The Washington Post reports that according to economist Rick Nevin, 65-95% of the variation in violent crime in 9 countries can be explained by lead. Nevins claims that crime rates rise and fall approximately 20 years after environmental lead concentrations increase and decrease, respectively. This theory isn’t new, but its relation to American politics is. Rudy Giuliani, former New York City mayor and current presidential candidate, claims that his law enforcement policies reduced homicides by 67% and total crime by 57% during his tenure as mayor from 1994-2001. Nevins argues that Giuliani benefited from policies in the 1960s to replace old lead windows (to reduce deadly falls) and in the 1970s and 1980s to reduce lead in paint and gasoline.

Lead is a neurotoxin that passes through the blood-brain barrier. Lidsky and Schneider report that lead mimics calcium in brain cells, disturbing endogenous calcium levels and inducing cytochrome C release from mitochondria. Lead also increases basal levels of acetylcholine, dopamine and amino acid neurotransmitters but reduces their activity-dependent release. Because children often put their hands in their mouths, they are susceptible to exposure to lead in paint. What are the behavioral effects of lead? Herbert Needleman, a psychiatrist at the University of Pittsburgh, reported increased lead levels in the bones of 11-year-old children with antisocial and delinquent behaviors and adolescents who had been through the penal system relative to their peers, suggesting that lead increases sociopathic behaviors and impulsivity.

Perhaps these data indicate that it’s time for political candidates to pipe down about their past achievements and speak up about how they intend to clean up the environment.

It’s double-blind or nothing when it comes to phase III clinical trials. Although placebo groups are absolutely vital to the clinical validity of medical treatments, a recent article in The Lancet has me thinking about the ethics of treating desperate patients with saline.

The subthalamic nucleus is overactive in people with Parkinson’s disease, presumably because it loses GABAergic input from the globus pallidus. Subthalamic nucleus lesions improve Parkinson’s disease symptoms. Kaplitt et al. generated a gene therapy agent that would silence but not destroy subthalamic nuclei neurons. They inserted glutamic acid decarboxylase (GAD), the enzyme responsible for GABA production, into a viral vector and injected it into subthalamic nuclei of people with Parkinson’s disease. In their phase I trial in 12 patients, the authors showed that their therapy was safe and virtually side-effect-free. Unlike most phase I trials, the authors also showed that their treatment was effective: intra-thalamic injections of the GAD agent reduced Parkinson’s symptoms.

That’s great news for a possible new treatment for Parkinson’s disease. But it also means that at some point soon, people with advanced Parkinson’s symptoms will volunteer for brain surgery and a 50% chance at treatment. Some would argue that even placebos have their upside, and I certainly understand their importance. I also understand that the patients who volunteer for these studies are often at the end of their medical ropes and are willing to roll the dice. I just feel for the folks who wake up 6 months after surgery and realize that their symptoms haven’t improved.

Enough with the cranes already! Richard Powers’s 2006 novel The Echo Maker, a National Book Award winner, is a great book to take to the beach (or the bench while the PCR machine is running), even if it is about 100 pages too long.

The Echo Maker follows Mark Schluter’s recovery from a mysterious car accident that leaves him with Capgras syndrome, the delusion that one’s loved ones have been replaced by imposters. His sister Karin calls in a celebrity neuroscientist, the Oliver Sacks-ish Dr. Gerald Weber, and all three struggle with issues of identity and self. Oh, and there are also those blasted cranes, who pass through this book far more frequently than they do the Nebraska Platte described in the novel.

Capgras is a fascinating disorder worthy of fiction and nonfiction alike. Ramachandran describes Capgras, in which familiar faces fail to illicit proper emotional responses, as the mirror to prosapagnosia, the inability to recognize faces. He has suggested that injury-induced Capgras (approximately 33% of all Capgras cases) may be caused by lesions of the connections between the inferior temporal cortex and the amygdala. Capgras patients, unlike people with amygdala lesions, show elevated galvanic skin responses to emotional stimuli, but not to pictures of people they know, suggesting that it’s not the amygdala itself that is affected, but the information flow to the amygdala from the visual cortex.

Like Ramachandran’s case study D. S. (not me, I swear), Mark Schluter doubles himself, describing his pre-injury self as ‘old Mark’, someone who looks very much like the person he used to be. Powers sprinkles references to 9/11 throughout The Echo Maker, perhaps implying that we are all quite different than the people we used to be. A point very elegantly made, but one that used way too many birds in the making.

TV’s Mr. Wizard, Don Herbert, died yesterday. He was the first (and favorite) science teacher for several generations of children. He will be greatly missed.

“One is 95 percent certainty, and the other is…50 percent and a feather”

According to attorney Kevin Conway (quoted in the Washington Post), that is the difference between the scientific and legal burden of proof that autism is related to childhood vaccines. Conway represents one of more than 4800 families who believe that a vaccine preservative caused autism in their loved ones and are suing for compensation from the Vaccine Injury Compensation Fund. The first test case is before the U. S. Court of Federal Claims today.

An editorial in the May issue described the lack of scientific data supporting this claim. However, the timing of this hearing is particularly interesting. Just days ago, the media generated a frenzy over Andrew Speaker, the American lawyer with a drug resistant form of tuberculosis who flew on commercial airplanes. Perhaps because vaccines have worked so well in combating diseases like polio, many in the west have been lulled into a false sense of security when it comes to diseases that are common in ‘the rest of the world’. The court should certainly weigh the global health impact of a generation of American children who are not vaccinated. Conversely, we must continue to ensure that despite our hysteria over modern health threats, like small pox and avian flu, vaccine companies test and retest their products (and publish their data!) before rushing them out to nervous consumers.

The Post points out the biggest losers in the autism court battle: autistic children. Although my heart goes out to the plaintiffs in this case, one has to wonder what therapies and services could be purchased for the price of the legal blame game.

If you could look into a crystal ball to find out how your life ends, would you? Yesterday, James Watson (yes, that James Watson) decided that he didn’t want to know. His personal genome was sequenced by 454 Life Sciences and the Human Genome Sequencing Center at the Baylor College of Medicine. Dr. Watson will make his entire genome publicly available with the exception of one gene: apolipoprotein E, the gene most strongly associated with Alzheimer’s disease, which killed his grandmother.

There is no correct answer to the genetic testing dilemma. The children and grandchildren of victims of diseases with much clearer genetic causes have struggled with this question for years. But if Watson’s genome announces the dawn of pharmacogenomics, many more of us will have to decide for ourselves what we do and what we don’t want to know.

Watson is not a man who shies away from controversy. Perhaps that is why I am slightly surprised by such a human decision from such a brazen pioneer.

As the news out of Blacksburg, Virginia continues to unfold, it is difficult not to reflect on the importance of mental health services for young adults. In a sad coincidence, a meta-analysis published today in JAMA suggests that despite earlier reports of increased suicide risk, the benefits of antidepressant treatment in children and young adults outweigh the risks. Bridge et al. report that antidepressants helped young people with major depressive disorder, obsessive compulsive disorder and anxiety and increased their risk of suicidal thoughts or attempts by less than 1%. Improved treatment protocols specific for children and teenagers will hopefully help young adults in need. Unfortunately, we all know that treatments can only help those who seek them.

Just a few weeks can separate a splash from a quiet ripple. On 5 April, Neuron and Nature both published articles reporting genetically targeted silencing of mammalian neurons. In Neuron, Lerchner et al. detailed drug-induced hyperpolarization of neurons expressing a C. elegans chloride channel within hours of treatment. In Nature, Zhang et al. reported light-induced hyperpolarization of neurons expressing an archaea opsin within milliseconds of illumination. The media took note of Zhang’s article, but not Lerchner’s.

To be fair, the two articles are quite different in scope. Zhang et al. reported not just inducible neuron silencing, but a neuron on/off switch. In the same neuron, the authors induced firing with a blue light-activated cation channel and inhibited endogenous firing with a yellow-light induced chloride pump. They turned behaviors on and off with blue and yellow light, respectively, in C. elegans expressing both the cation channel and the chloride pump. The ability to control neuron function is nothing short of stunning and will undoubtedly impact both bench and bedside.

Although their scope was much smaller, Lerchner et al. approached neuronal silencing cleverly. Ivermectin is a chloride channel agonist in C. elegans, but not mammals, making it a potent antiparasitic agent that literally puts worms to sleep, sparing mammalian hosts. The authors silenced mammalian neurons expressing the C. elegans ivermectin-gated chloride channel and suppressed behavior with systemic treatment of ivermectin.

Systemic drug treatment is virtually guaranteed to take longer than illumination to achieve inhibition. And an off switch alone can’t compare to the deluxe on/off model. But I can’t help wondering if I’d be more excited about Lerchner’s article if it came out a few weeks earlier.

There is one interesting postscript to Zhang’s amazing achievement. Han and Boyden reported an identical yellow-light induced chloride pump earlier in the month in PLoS ONE. They examined the properties of blue and yellow light-induced excitation and inhibition in cultured hippocampal neurons. Although Han and Boyden don’t show any in vivo data, their study technically preceded Zhang et al. So, in the grand scheme of things, who will be credited with the discovery? Maybe timing isn’t everything.

We may have to thank body builders for the next big breakthrough in the battle against Parkinson disease. Companies that market powders and potions to those obsessed with their glutes and pecs claim that the dietary supplement creatine changes physiques. However, the NIH National Institute of Neurological Disorders and Stroke (NINDS) recently announced a phase III clinical trial examining the ability of creatine to slow symptom progression in people with Parkinson disease.

Although its body-bulking effect may be caused by simple weight gain, creatine is thought to boost exercise performance. Phosphocreatine donates phosphate groups to ADP, increasing the supply of ATP available in muscle, which allows muscles to work longer and harder.

Creatine is also neuroprotective. Klivenyi et al. reported that creatine prevented neuron loss but did not affect muscle weight in a mouse model of ALS. Zhu et al. reported that ischemia caused smaller stroke volumes in mice treated with creatine relative to vehicle. Ischemia induced less cytochrome c release and caspase activation in creatine-treated relative to vehicle-treated mice.

Creatine performed well in small clinical trials. Now NINDS plans to study 1720 people in the early stages of Parkinson disease in a double-blind study of creatine’s effects. This study, the first of a series of clinical trials called NIH exploratory trials in Parkinson disease (NET-PD), is slated to last five to seven years.

In response to my comments, Juan Carlos Lopez had this reply on Spoonful of Medicine:

Candidate genes? We already have many more candidate genes than we know what to do with. I’d argue that candidate genes are, in fact, part of the “genetic noise” Debra refers to.

What this field needs is, among other things, new animal models that allow us to make more thoughtful experiments on the biological basis of psychiatric disease.

In the absence of good models in which to test the functional relevance of whatever genes the screening process identifies, the massive investment that Apoorva highlighted will bring rather paltry returns.

He makes an excellent point, but I’m sticking to my guns. Groups of genes that are subtly affected (not wiped out entirely) would not have been found in the small populations studied thus far. Furthermore, the absence of good animal models underscores the need for more information on variation in the only disease model we have: the human.