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Secondly, this study convincingly shows that pharmacologic treatments could poten-tially induce regression of established AAAs. Ongoing research efforts should be redi-rected toward achieving a better understand-ing of matrix deposition and connective tissue repair in AAAs, rather than focusing solely on proteinase-mediated destruction of connective tissue. Issues to be considered include: what mechanisms regulate deple-tion and restoration of smooth muscle cells in aneurysm tissue; how do circulating progenitor cells affect vascular repair; and how does repair of connective tissue lead to aneurysm sac contraction.

Furthermore, as this study used animal models of AAAs, it may not have reproduced all aspects of aneurysmal degeneration in humans, including important limitations on vascular repair that may exist in the elderly population typically afflicted with AAAs.

Clinical experience with endovascular treat-ment of AAAs provides evidence that the aneurysm sac often heals (contracts) after successful exclusion from systemic bloodpressure12. Therefore, it now seems plausible that similar reparative effectsmight be achievable using cellular or phar-macologic strategies capable of inducingregression of AAAs13.

Finally, from a clinical perspective, concerns remain that enthusiasm for endovascular repair of AAAs may lead to wider application of this treatment in individuals with small AAAs14. This is a concern because imaging surveil-lance has already proven to be a safe treatment for small AAAs and endovascular repair is not free of risks. The demonstration that a phar-macologic strategy can induce regression of aneurysms in experimental AAAs should now temper this enthusiasm. Hopefully, pharma-cologic therapy for small AAAs will be evalu-

ated in clinical trials before it is concluded that endovascular repair is the treatment of choice for all individuals with AAAs.

1. Thompson, R.W., Geraghty, P.J. & Lee, J.K. Curr. Prob. Surg. 39, 93–232 (2002).

2. Yoshimura, K. et al. Nat. Med. 11, 1330–1338 (2005).

3. The UK Small Aneurysm Trial Participants. Lancet 352, 1649–1655 (1998).

4. Lederle, F.A. et al. N. Engl. J. Med. 346, 1437–1444 (2002).

5. Wassef, M. et al. J. Vasc. Surg. 34, 730–738 (2001).6. Pyo, R. et al. J. Clin. Invest. 105, 1641–1649

(2000).7. Longo, G.M. et al. J. Clin. Invest. 110, 625–632

(2002).8. Manning, M.W., Cassis, L.A. & Daugherty, A. Arterioscler.

Thromb. Vasc. Biol. 23, 483–488 (2003).9. Mosorin, M. et al. J. Vasc. Surg. 34, 606–610

(2001).10. Baxter, B.T. et al. J. Vasc. Surg. 36, 1–12 (2002).11. Han, Z. et al. J. Clin. Invest. 108, 73–81 (2001).12. Matsumura, J.S., Pearce, W.H., McCarthy, W.J. & Yao,

J.S. J. Vasc. Surg. 25, 113–123 (1997).13. Allaire, E. et al. Ann. Surg. 239, 417–427 (2004).14. Zarins, C.K. et al. Eur. J. Vasc. Endovasc. Surg. 29,

496–503 (2005).

Oxidative stress is the new stressJay A Gingrich

Emotional stress may increase anxiety, but in mice, a different kind of stress—oxidative stress—may also contribute to anxious behavior.

Anxiety and fear are useful when the situation warrants. The stress of an upcoming exam prods the student to master the test material to allay anxiety. Fear, and the self-preserving actions it elicits, is adaptive when an organism is faced with life-threatening situations.

A brief stint in a psychiatrist’s consulting room, however, will demonstrate that not all fears and anxieties are useful. Many people are crippled by inappropriate anxiety and fear characteristic of a variety of disorders, rang-ing from the crescendo of dread and arousal of the sympathetic nervous system seen in panic disorder to the hypervigilance, avoid-ance and flashbacks seen in post-traumatic stress disorder—to the inappropriate fear of blood, snakes, heights or enclosed spaces that typifies the various phobias. Although these clinical syndromes are common, their under-lying cause remains elusive.

It has long been established that genetic contributions increase the vulnerability

The author is in the Department of Psychiatry,

College of Physicians and Surgeons, Columbia

University, New York, New York 10032, USA.

E-mail: jag46@columbia.edu

Figure 1 How to recognize an anxious mouse. Because mice are nocturnal animals, they prefer darkness to light; but they also have an innate drive to explore new environments. Exploring a new, riskier environment exposes the mouse to a predator threat but also increases the possible discovery of food or mates. Laboratory tests, such as dark-light choice and open field, are used to infer the anxiety state of the mouse by measuring how much time is split between safe and risky behavior. The dark-light choice test is performed in a divided chamber with a portal. The safe half of the chamber is dark or dimly lit (dark blue); the risky side is open and brightly lit (light blue). The open-field test uses a brightly lit open-topped chamber. Anxious mice will spend less time exploring the more exposed, central portion of the environment (light blue) and spend more time near the safety of the boundary walls (dark blue). Hovatta et al. used these tests to determine how genetic differences in mice contribute to anxiety. They found that mice with lower amounts of glyoxalase 1 (Glo1) and glutathione reductase 1 (Gsr)— two enzymes that modulate the levels of oxidative stress— spend more time in the riskier sections of both environments. Likewise, mice with increased levels of these enzymes preferred safety. The authors conclude that high levels of oxidative stress may contribute to anxious behavior.

Safety RiskExploration

Glo1 and Gsr

Glo1 and Gsr

Danger

Safety

Dark-light choice test Open field test

Avoidance

Safety Risk Safety

Risk

Safety

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ie R

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to anxiety disorders, but the precise genes involved are unknown. In a study published online October 23 in Nature, Hovatta et al. report an unexpected twist in the genetics of anxiety—the expression levels of two enzymes, glyoxalase 1 (Glo1) and glutathi-one reductase 1 (Gsr), are highly correlated with anxiety levels1. Neither Glo1 nor Gsr are the usual suspects in anxiety disorders, as they are not the targets of the commonly prescribed anxiety medications. They are, however, related to stress, but not the kind we think of as associated with anxiety dis-orders. Rather, these enzymes modulate the levels of oxidative stress—the kind of stress produced by free oxygen radicals.

Anxiety disorders, some of the most common of psychiatric disorders, affect an estimated 28% of the U.S. population2. In addition, anxi-ety symptoms often occur in individuals with other conditions such as depression and sub-stance abuse. The mainstays of treatment are benzodiazepines and serotonin-selective reup-take inhibitors (SSRIs). Benzodiazepines inter-act with gamma amino butyric acid (GABA) A receptor, a ligand-gated ion channel, and increase the probability of channel opening and hyperpolarizing neurons. Although clini-cally useful, benzodiazepines are also liable to dependence, tolerance and unwanted sedation. SSRIs inhibit the plasma membrane serotonin transporter and increase extracellular levels of serotonin. Although the treatment of choice for obsessive-compulsive disorder, panic dis-order, generalized anxiety disorder and social phobia, SSRIs require weeks to work and are not without side effects.

The paradox of psychiatry as a medical disci-pline is that although there are effective medi-cations with clear biochemical actions, how these biochemical effects translate into thera-peutic benefits remains largely unknown. The corollary is also true—the underlying patho-physiology of psychiatric disorders is equally elusive despite significant advances in the efficacy of treatments. Thus, any new insight into the possible causes of these disorders is welcome news.

In the absence of new hypotheses, most of the current work in anxiety disorders focuses on uncovering abnormalities in the GABA and serotonin systems. Some of these inquiries have been enlightening. A polymorphism in the promoter of the gene encoding the serotonin transporter reduces transcriptional efficiency3. Individuals carrying the low-expressing vari-ant have more ‘neurotic’ personality traits on standard surveys—traits that are highly related to anxious temperament.

Additionally, mice lacking 5-HT1A receptors or the serotonin transporter were more anx-

Memory stem cells sustain disease Xue-Zhong Yu & Claudio Anasetti

A rare memory stem cell has been discovered that sustains graft-versus-host disease in animal models (pages 1299–1305)

After antigen challenge, activated CD8+

T cells clonally expand and acquire effector functions. After the initial response, most

T cells are rapidly cleared through apop-tosis, but a few survive and develop into memory cells. The identity of CD8+ T cells that have the potential to develop into long-lived memory cells is actively pursued1— these cells may hold the key to sustained graft-versus-host disease (GVHD) after hematopoietic cell trans-plantation.

In this issue, Zhang et al. identify a sub-set of postmitotic CD8+ T cells that persist throughout the course of GVHD and are

Xue-Zhong Yu is at the Immunology Program

and Claudio Anasetti is at the Experimental

Therapeutics Program, Division of Blood

and Marrow Transplantation, Department of

Interdisciplinary Oncology, Moffitt Cancer Center

and Research Institute and University of South

Florida, Tampa, Florida 33613, USA. E-mail:

yuxz@moffitt.usf.edu or anasetc@moffitt.usf.edu

ious than their wild-type littermates4–8. Later studies showed that in these mice, disrupted early development caused increased anxiety and depression—suggesting that serotonin regulates development of anxiety-modulating brain systems9,10. Mice lacking components of the GABA system also have increased anxiety states11–15. In addition, mice with alterations in various other neurotransmitters—such as corticotropin-releasing hormone and neuroki-nin systems —also exhibit altered anxiety-like responses16.

Despite the apparent diversity and com-plexity of these findings, there were few real surprises. Most of these studies were linked to traditional neurotransmitter systems and their receptors. Thus, the findings of Hovatta et al. are all the more provocative, as they do not implicate neurotransmitters. Instead, the authors correlate Glo1 and Gsr—two run-of-the-mill enzymes that protect cells from oxida-tive damage—with anxiety.1

Their case relies on three lines of evidence. First, after screening several brain regions in dif-ferent mouse strains with a range of innate anxi-ety, they showed that expression levels of Glo1 and Gsr positively correlated with the anxiety state of the animal. Second, they confirmed that enzymatic activity of Glo1 and Gsr was increased in mice with higher anxiety. Third, experimental upregulation of Glo1 and Gsr increased anxiety in mice, and reduction in expression produced less anxious mice (Fig. 1).

As with other studies with unexpected find-ings, this work has raised more questions than it has answered. What is the mechanism by which these enzymes influence anxiety state?

Glo1 and Gsr were identified based on their expression levels in several brain regions, but the effect on anxiety could be recreated simply by manipulating expression in a single region. Perhaps these enzymes only act in specific structures. Do Glo1 and Gsr interact, either physically or functionally, with more tradi-tional neurotransmitter modulators of anxiety? And will Glo1 and Gsr also prove relevant to human anxiety disorders? If so, could these enzymes provide the pharmaceutical industry with new drug targets?

For the moment, Hovatta et al. have uncov-ered an unsuspected new set of players in the complex control of human anxiety—giving new meaning to the connection between anxi-ety and stress.

1. Hovatta I. et al. Nature advance online publication 23 October 2005 (doi 10.1038/nature04250).

2. Kessler, R.C. et al. Arch. Gen. Psychiatry 62, 593–602 (2005).

3. Lesch, K.P. et al. Science 274, 1527–1531 (1996).4. Holmes, A. et al. Neuropsychopharmacology 28,

2077–2088 (2003).5. Lira, A. et al. Biol. Psychiatry 54, 960–971 (2003).6. Parks, C.L. et al. Proc. Natl. Acad. Sci. USA 95,

10734–10739 (1998).7. Ramboz, S. et al. Proc. Natl. Acad. Sci. USA 95,

14476–14481 (1998).8. Heisler, L.K. et al. Proc. Natl. Acad. Sci. USA 95,

15049–15054 (1998).9. Ansorge, M. S. et al. Science 306, 879–881 (2004).10. Gross, C. et al. Nature 416, 396–400 (2002).11. Rosahl, T.W. Curr Drug Targets CNS Neurol. Disord. 2,

207–212 (2003).12. Mombereau, C. et al. Neuroreport 16, 307–310

(2005).13. Mombereau, C. et al. Neuropsychopharmacology 29,

1050–1062 (2004).14. Kash, S.F. et al. Proc. Natl. Acad. Sci. USA 96, 1698–

1703 (1999).15. Chandra, D. et al. BMC Neurosci. 6, 30 (2005).16. Clement, Y. et al. Brain Res. Bull. 57, 57–71 (2002).

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