All posts in Neurotrophic Factors

Neurturin

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Because of the ability of neurotrophic factors (NTFs) to protect dying neurons, scientists believe that these proteins could one day be used to treat neurodegenerative disorders such as Huntington’s disease (HD) and Parkinson’s disease. One NTF currently being examined is neurturin, a member of the Glial cell line-derived neurotrophic factor (GDNF) family. Studies performed in living organisms ( in vivo) suggest that neurturin is not essential for survival. Mice born without neurturin are able to grow, reproduce and survive similar to mice born with neurturin. However, these in vivo studies of mice provide evidence that neurturin is essential for certain neural functions, such as controlling the sensory nerves. Additionally, neurturin has been shown to promote the survival of certain neurons in vitro, including those found in the sympathetic nervous system, the dorsal root ganglion, and the midbrain.

Does neurturin affect the progression of HD?^

Neurturin and its receptor can be found in the striatum, the region of the brain that is greatly affected by HD (Click here to see our section on the effects of HD on striatal neurons). One in vivo study compared the protective effects of neurturin and GDNF (the namesake NTF of the GDNF family) by engineering cells to serve as NTF production factories and grafting, or transplanting, these cells into mice. These mice were then given injections of chemicals intended to mimic the excitotoxic model of HD (Click here to see our section on the excitotoxic model). Neurturin was not only more effective than GDNF at rescuing a specific type of striatal neurons, but the former NTF also reduced the extent of neuronal damage caused by excitotoxic damage. Interestingly, the study found that neurturin and GDNF interacted with striatal neurons in different ways, suggesting that these factors may work together to protect these neurons. Indeed, GDNF has been found to be more effective than neurturin at protecting certain populations of striatal interneurons, nerve cells that connect afferent neurons (those that carry sensory information to the brain) and efferent neurons (those that carry nerve impulses away from the brain). Future research may look at ways of combining different NTFs to more effectively preserve damaged neurons.

Can neurturin one day be used to treat human patients with neurodegenerative diseases?^

The therapeutic application of neurturin is currently being investigated in a series of clinical trials run by the drug company Ceregene. A major challenge to the therapeutic use of neurturin and other NTFs is figuring out how to sustainably deliver these compounds into the brain. Because NTFs do not cross the blood-brain barrier, they cannot be administered orally. One proposed method has been the use of viral vectors to deliver a gene engineered to over-express neurturin into the striatum (For more information on viral vectors, click here). These genes can be thought of as neuturin factories, designed to increase the levels of neuturin produced by these cells. Once introduced, viral vectors with these genes have been shown to consistently and selectively deliver neurturin to dying neurons in cultures. Scientists at Ceregene have demonstrated that the viral vector delivery of neuturin (trade name: CERE-120) protected damaged neurons in mice and monkey models of Parkinson’s disease. Based on these results, CERE-120 for Parkinson’s disease is currently being evaluated in Phase II clinical trials. However, recent results have not been encouraging—patients treated with CERE-120 failed to show significant improvements over those who did not receive treatment. As a result, Ceregene is currently evaluating their future plans for CERE-120.

CERE-120 has also been proposed as a potential treatment for HD. The administration of CERE-120 to mouse models of HD showed evidence of both structural and functional protection of nerve cells—the mice not only showed decreased rates of neuron death, but also exhibited improved motor control. Positive results have been observed both in transgenic HD rodents, as well as rodents chemically induced to show symptoms of HD. The use of CERE-120 in humans to treat HD is currently being evaluated in pre-clinical development. Updates on the progress of CERE-120 will be added to this page as necessary.

For Further Reading^

  • Alberch, J., Pérez-Navarro, E., & Canals, J.M. (2002) Neuroprotection by neurotrophins and GDNF family members in the excitotoxic model of Huntington’s Disease. Brain Research Bulletin 57(6): 817-822.
    • This paper reviews the research on the potential of NTFs in the GDNF family to protect neurons in animal models of Huntington’s disease. Primarily written for scientists.
  • Ceregene. Pipeline. http://www.ceregene.com/pipeline.asp. Accessed October 7, 2009.
  • Gasmi, M., Brandon, E.P., Hergoz, C.D. et al. (2007) AAV2-mediated delivery of human neurturin to the rat nigrostriatal system: Long-term efficacy and tolerability of CERE-120 for Parkinson’s disease. Neurobiology of Disease 27: 67-70.
    • This very technical article examines the effect of using a viral vector (CERE-12) to deliver neurturin to rats in order to treat Parkinson’s disease-like symptoms.
  • Heuckeroth, R., Enomoto, H., Grider, J., et al. (1999) Gene targeting reveals a critical role of neurturin in the development and maintenance of enteric, sensory, and parasympathetic neurons. Neuron 22(2): 253-263.
    • This article seeks to characterize the normal functions of neurturin by examining mice incapable of producing this NTF. Although the language is technical at times, the article is pretty easy to understand.
  • Kordower, J.H., Hergoz, C.D., Dass, Biplob, et al. (2006) Delivery of neurturin by AAV2 (CERE-120)-mediated gene transfer provides structural and functional neuroprotection and neurorestoration in MPTP-treated monkeys. Annals of neurology 60: 706-715.
    • This technical article examines the effectiveness of CERE-120 in monkey models of PD. New treatments are usually tested on monkeys before they go into clinical trials.
  • Pérez-Navarro, E., Akerud, P., Marco, S., et al. (2000) Neurturin protects striatal projection neurons but not interneurons in a rat model of Huntington’s Disease. Neuroscience 98(1): 89-96.
    • This article investigates the ability of neurturin to protect striatal neurons in rodent models of HD. The language can get very technical, but its conclusions are very clear and easy to understand.
  • Ramaswamy, S., McBride, J.L., Han, I., et al. (2008) Intrastriatal CERE-120 (AAV-Neurturin) protects striatal and cortical neurons and delays motor deficits in a transgenic mouse model of Huntington’s disease. Neurobiology of Disease 34: 40-50.
    • This article examines the effectiveness of CERE-120 in the treatment of transgenic mice with the mutated Huntington gene. The introduction is pretty accessible to all readers.
  • Ramaswamy, S., McBride, J.L., Hergoz, C.D. (2007) Neurturin gene therapy improves motor function and prevents death of striatal neurons in a 3-nitropropionic acid rat model of Huntington’s disease. Neurobiology of Disease 26: 375-384.
    • This article uses CERE-120 to treat rats chemically induced to exhibit HD-like symptoms. The writing is quite technical throughout.

-Y. Lu, 1-17-10

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Neurotrophic Factors and Huntington's Disease

Neurotrophic factors are proteins that promote the development, maintenance and survival of neurons in the brain. These factors have been shown to increase the function of nerve cells as well as protect diseased neurons from dying. There are often higher levels of neurotrophic factors in areas with local neuronal damage, meaning that neurotrophic factors might be involved in neuronal rescue and regeneration. A chronic absence of these essential proteins eventually leads to apoptosis, the death of specific populations of neurons in the brain.

cells hypothesis kinases

NGF Superfamily (neurotrophins)^

In 1987, a neutrophic factor called nerve growth factor (NGF) was discovered. The study of NGF led to the Neurotrophic Factor Hypothesis, which suggested that neurons must compete with each other for specific survival factors. A useful analogy would be to imagine growing two plants in a pot. These two plants must compete for the limited amounts of nutrients in the soil, and the plant better able to take up nutrients would be more likely to survive. The Neurotrophic Factor Hypothesis proposes that the availability or absence of neurotrophic factors determines whether a given neuron will live or die. Today, researchers believe that almost all cells are likely to depend on their interactions with neighboring cells for survival. Since the discovery of NGF, three other molecules of this family have been characterized—brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4). The first three neurotrophins (NGF, BDNF and NT-3) are expressed in the basal ganglia, which means that they may be involved in neurodegenerative disorders that affect that region of the brain, such as Huntington’s disease (HD).

TGFß Superfamily^

The transforming growth factor-ß (TGFß) superfamily consists of three subfamilies of neurotrophic factors. Of particular interest are the glial cell line-derived neurotrophic factor (GNDF) family, which consists of four proteins, GNDF, neurturin, persephin and artemin. These factors are known to affect different parts of the central nervous system. For example, GNDF and neuturin have been found in the striatum and have been shown to promote the survival of motor neurons, which are commonly affected in HD.

Neurokine Superfamily^

The neurokine superfamily includes proteins such as ciliary neurotrophic factor (CNTF), which has functions in the central nervous system. Synthesized by astrocytes, CNTF is believed to be a key player in the nervous system’s response to injury and has been shown to protect damaged neurons in vitro.

Non-neuronal Growth Factors^

Although non-neuronal growth factors affect many different physiological processes, they have been found at high concentrations in the nervous system. For example, almost all regions of the brain exhibit receptors for insulin-like growth factor-1 (IGF-1), a protein that has been shown to be a survival factor for neuronal cells in laboratory cultures.

The Importance of Receptors^

In order for neurotrophic factors to affect neurons, they must first bind to their respective receptors. The structure, function and location of these receptors vary greatly between different neurotrophic factors. For example, in the NGF superfamily, there are two main types of receptors— 1) tyrosine receptor kinases that bind specific neurotrophins with high affinity, meaning very tightly and, 2) the p75 neurotrophin receptor that binds all four types of neurotrophins with relatively low affinity, or less tightly. The low affinity p75 receptor appears to enhance the signaling of the high-affinity tyrosine receptor kinases. Scientists are studying not only how these receptors respond to their neurotrophic factors, but also how they interact with each other. Understanding the function of these receptors is crucial for developing therapeutic uses for neurotrophic factors, as these protective molecules are only valuable if they are recognized by the targeted neurons.

Neurotrophic Factors and Huntington’s Disease^

Researchers are interested in the protective qualities of neurotrophic factors because of their role in neurodegenerative disorders, such as Huntington’s disease (HD). One of the most striking physiological characteristics of HD is the loss of neurons in the striatum, a component of the basal ganglia system that organizes motor movement. In particular, there is a loss of the spiny neurons that compose 95% of the striatum. In recent years, there has been considerable research not only on the affect of HD on neurotrophic factor levels, but also the protective roles that neurotrophic factors can play in preventing neurodegeneration. For example, mutated huntingtin has been shown to down-regulate the expression of BDNF. In turn, the decreased expression of BDNF in HD has been implicated in the progressive loss of neurons in the striatum (For more information on this topic, see the section on BDNF). Transplanted cells in the striatum that are engineered to over-express GNDF and neurturin have also been shown to protect neighboring neurons from excitotoxic attacks (for more information, see our section on the excitatoxic model of Huntington’s disease. In cellular models of HD, treatment with CNTF has been shown to protect spiny neurons from the apoptotic pathway induced by mutant huntingtin. (To read more about the apoptotic pathway, click here.) These examples highlight not only the complex interactions between HD and neurotrophic factors, but also the therapeutic potential of these protective proteins.

However, there are still obstacles to developing effective neurotrophic factor-based therapies for neurodegenerative diseases. Although the protective effects of neurotrophic factors are well-known, the therapeutic potential of these proteins will depend on the ability to effectively deliver these factors into the desired regions of the brain. Neurotrophic factors do not easily cross the blood-brain barrier and thus, must be administered in large doses in order to have an effect on the target region(s). To avoid technical challenges and side effects of large doses, scientists are looking for ways to directly introduce neurotrophic factors into regions with damaged neurons. One method is directly injecting neurotrophic factors into the brain. Another strategy involves injecting genetically engineered cells that over-express certain neurotrophic factors into the central nervous system. However, these methods are limited by their invasiveness and the extent to which these neurotrophic factorstravel in the brain. Recent research has looked into using viral vectors to provide continuous, long-term delivery of neurotrophic factors. This technique would incorporate the DNA code to make neurotrophic factors into the genome of a virus. These viruses then enter our body’s neurons and use the nerve cells’ own machinery to make the specific neurotrophic factors encoded by the DNA. Despite the challenges, there is a great deal of interest in one day using neurotrophic factors as a therapy for HD.

Further Reading^

  • Alexi, T. et al. (2000) Neuroprotective strategies for basal degeneration: Parkinson’s and Huntington’s diseases. Progress in Neurobiology 60: 409-470.This paper provides an exhaustive overview of the many different factors that are being examined for therapeutic potential in Parkinson’s and Huntington’s disease.
  • Dawbarn, D. & Allen, S.J. (2003) Neurotrophins and neurodegeneration. Neuropathology and Applied Neurobiology 29: 211-230.This paper focuses on the role of neurotrophins in three neurodegenerative diseases: Alzheimer’s, Parkinson’s and Huntington’s diseases. There is a large focus on recent experiments.
  • Chao, M.V., Rajagopal, R. & Lee, F.S. (2006) Neurotrophin signaling in health and disease. Clinical Science 110: 167-173.This article goes into detailed descriptions of how neurotrophic factor signaling works, but also has a relatively accessible section on the therapeutic potential of neurotrophins.
  • Alberch, J., Pérez-Navarro, E. & Canals, J.M. Neurotrophic factors in Huntington’s disease. Progress in Brain Research 146: 195-229.This article provides a detailed review of the research being done on the role of neurotrophic factors in HD. The language is very technical, with very frequent references to the findings of recent experiments.
  • Levy, Y.S., Gilgun-Sherki, Y., Melamed, E. & Offen, D. (2005) Therapeutic potential of neurotrophic factors in neurodegenerative diseases. Biodrugs 19: 97-127.This paper provides an overview of all the neurotrophic superfamilies. While some of the language is very technical, it does a good job of summarizing many different neurotrophic factors.
  • Weis, J., Saxena, S., Evangelopoulos, M.E. & Kruttgen, A. (55) Trophic factors in neurodegenerative diseases. Life 55: 353-357.This article goes into considerable detail about the mechanisms of neurotrophic factor signaling, especially in neurodegenerative diseases.
  • Huang, E.J. & Reichardt, L.F. (2001) Neurotrophins: Roles in neuronal development and function. Annual Review of Neuroscience 24: 677-736.This article provides an extremely comprehensive overview of neurotrophins.

-Y. Lu , 6/18/2009

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Brain-derived neurotrophic factor (BDNF)

Neurotrophic factors are a family of proteins that are responsible for the growth and survival of nerve cells during development, and for the maintenance of adult nerve cells. Animal studies and test tube (in vitro) models have shown that certain neurotrophic factors are capable of making damaged nerve cells regenerate. Because of this capability, these factors represent exciting possibilities for reversing a number of devastating brain disorders, including Alzheimer’s disease, Parkinson’s disease, Lou Gehrig’s disease, and Huntington’s Disease (HD). (For more information on how HD relates to Alzheimer’s and Parkinson’s, click here.) Currently, scientists are looking for ways to harness neurotrophic factors and somehow induce the damaged nerve cells to regenerate in order to improve the symptoms of people with neurological disorders.

One neurotrophic factor that is particularly relevant to HD is Brain-derived neurotrophic factor (BDNF). BDNF levels are decreased in the brains of HD patients, which might be partly responsible for the degenerative processes of HD. Researchers have recently discovered a link between BDNF, mutant huntingtin, and excitotoxicity, a process by which brain cells die after stimulation. The mutant huntingtin protein invariably leads to the death of nerve cells in the striatum, the region of the brain needed for movements; however, how mutant huntingtin does this damage is unclear. One possibility is that mutant huntingtin lowers levels of BDNF, making nerve cells more susceptible to injury and death. Therefore, therapeutic approaches aimed at increasing BDNF production may be able to counteract the effects of mutant huntingtin and prevent a significant amount of the neurodegeneration that would otherwise occur in HD. (For more information on huntingtin protein, click here.)

What role does BDNF play in HD pathology?^

BDNF has been shown to play a role in neuroplasticity, which allows nerve cells in the brain to compensate for injury and new situations or changes in the environment. (For more information on neuroplasticity, click here.) The central nervous system (CNS) has a greater ability to recover from insult or injury than scientists had previously thought. For decades, the prevailing view was that the brain stopped developing after the first few years of life. Connections between the brain’s nerve cells could only be formed during a critical period early in life. After this critical period, it was thought that the brain was unable to form new connections. Thus, if a particular area of the adult brain was damaged or injured, nerve cells would not be able to regenerate, and the functions controlled by that area would be lost forever. However, new research suggests that this view is not entirely correct. Researchers now recognize that the brain continues to reorganize itself by forming new neural connections throughout life. Neurotrophic factors, such as BDNF, promote the survival and aid in the regeneration of adult neurons.

As mentioned above, the mutant huntingtin protein is harmful to striatal nerve cells in the brain. It also decreases transcription of BDNF, which results in a decrease BDNF production in people who have HD. Nerve cells require BDNF to survive, but also to regenerate. Less BDNF means less neuroplasticity so the striatal nerve cells are less capable of compensating for injuries. By lowering levels of BDNF in the brain, mutant huntingtin acts as a devastating double-edged sword. First, nerve cells die because there isn’t enough BDNF to effectively combat neurodegeneration. Second, nerve cells are not able to regenerate because there still isn’t enough BDNF. It therefore appears that BDNF plays a crucial role in the degenerative process of HD.

How does BDNF work?^

In the brain, BDNF is released by either a nerve cell or a support cell, such as an astrocyte, and then binds to a receptor on a nearby nerve cell. (For more information on HD neurobiology, click here.) This binding results in the production of a signal which can be transported to the nucleus of the receiving nerve cell. There, it prompts the increased production of proteins associated with nerve cell survival and function.

Can exercising promote BDNF production?^

Scientists are increasingly recognizing the capacity of physical activity to maintain and compensate for deterioration of nerve cell function. Numerous animal studies have reported that voluntary exercise leads to increased BDNF production. In rats, several days of voluntary wheel-running increased levels of BDNF in the hippocampus. This finding is surprising considering that the hippocampus is a structure normally associated with higher cognitive functions such as emotion and memory rather than motor activity. The changes in BDNF levels were found in nerve cells within days in both male and female rats and were sustained even several weeks after exercise.
Similarly, scientists studying HD in mouse models found that HD mice given the opportunity to exercise expressed more BDNF in the striatum than HD mice that didn’t exercise. This is notable because people with HD have particularly low levels of BDNF in the striatum, which is thought to be part of the reason that the striatum is the main site of neurodegeneration in people with HD. Furthermore, motor and cognitive symptoms set in later for HD mice that ran,

In order for exercise to be used as a therapeutic strategy the type and duration of exercise would need to be determined and probably individualized to each patient. There is debate over what intensity of exercise is best to promote brain health. Although previous reports showed that only rigorous exercise, like treadmill running, stimulated BDNF expression, researchers have more recently found that even a light exercise routine may be sufficient. The downside of high intensity is that sometimes this kind of exercise can be a stressful experience that increases the release of stress hormones, thereby canceling the BDNF-promoting effects of exercise. Also, many individuals are simply unable to perform rigorous exercise. These new reports are very encouraging because they indicate that everyone can enjoy the benefits of exercise by simply engaging in light activities such as walking or doing yard work. (For more information on exercise and HD, click here).

Can BDNF be used to treat HD?^

The discovery of the relation between huntingtin and BDNF is a major step in the path to finding a treatment for HD. Previously, it was thought that mutant huntingtin gained a new function that caused neurodegeneration in the brain. However, researchers now know that HD is caused, not only by this toxic gain of function of mutant huntingtin, but also by a loss of function of normal huntingtin. Normal huntingtin allows BDNF production and plays a role in moving BDNF to the places it is needed most. In the absence of normal huntingtin, BDNF production drops drastically. This realization is a major step toward HD treatment because it indicates that therapeutics need to be aimed not only at preventing mutant huntingtin toxicity, but also at restoring normal huntingtin function.

A simple way to restore the loss of normal huntingtin function in the case of decreased BDNF production would be to administer BDNF itself. However, when BDNF is taken by routes common for other drugs, such as orally or injections into the body, it can’t reach the brain where it is needed; there is a barrier – the blood-brain barrier – that makes it difficult for substances to pass between the body and the brain. So numerous laboratories are currently trying to develop ways to deliver BDNF to the brain. However, there are still several steps that need to be taken before a drug can be developed based on this research. Scientists need to understand exactly how huntingtin “communicates” to the BDNF gene to increase its activity. Trials are already under development to deliver BDNF via gene therapy to HD transgenic mice and researchers are confident that research in this area will progress rapidly.

Research on BDNF Inducers^

While BDNF itself is not yet a viable treatment for HD, scientists are actively researching BDNF inducers, which are drugs that increase levels of BDNF in the brain.

Citalopram (Celexa)^

Citalopram is an anti-depressant that is currently on the market to treat people with depression, and goes by the brand-name Celexa. Citalopram is a particular type of anti-depressant called a selective serotonin reuptake inhibitor (SSRI). This class of anti-depressants are believed to raise BDNF levels; SSRIs cause an increase in serotonin levels, which causes nerve cells to make more BDNF. Therefore, SSRIs are being investigated for their potential ability to slow the progression of HD – as described in more detail here.

Scientists are now investigating how citalopram might help people with HD in a phase II clinical trial called CIT-HD. Scientists will study the effect of citalopram on attention, thinking, muscle movements, and daily activities. The study will last for 20 weeks, and is currently enrolling participants. For more information about CIT-HD, or to participate in the trial, please click here.

Ampakines^

Ampakines are a type of drug that have recently caught the eye of the scientific community for their potential to raise BDNF levels. Cortex Pharmaceuticals Inc. is actively developing and researching the use of ampakines for treatment of various neurological disorders, including HD.

(Simmons et al. 2010): Scientists treating HD mice with ampakines are finding promising results. HD mice injected with ampakines twice a day have normal levels of BDNF. Additionally, several other symptoms of HD, such as striatal atrophy and aggregation of the mutatnt huntingtin protein, were decreased by ampakine treatment. These scientists also tested the behavior of the mice to see whether ampakine treatment was helpful in fighting the effects of the HD mutation. The motor symptoms that HD mice display were significantly improved in HD mice that were given ampakine treatment before their symptoms had begun. Another symptom that HD mice and patients display – problems with memory – seemed to be aided by ampakine treatment. Further studies are needed to verify these findings, but this study and others suggest that ampakines are a promising avenue of research.

Cystamine^

Cystamine is a drug that might combat HD in several ways. Apart from the fact that it is thought to raise levels of BDNF, cystamine might also inhibit protein aggregation (the process by which ‘clumps’ of mutant huntingtin form), and has antioxidant properties. Raptor Pharmaceuticals is currently studying cystamine in phase II clinical trials. For more information on cystamine and the on-going clinical trial, please read the HOPES article here.

For further reading^

1. Connor, J. et al. (1997). Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport. Society for Neuroscience 17(7): 2295-2313.
This article is fairly complex. It describes the likely method through which BDNF exerts its effects within the brain.
2. Gomez-Pinilla, F., Ying, Z., Roy, R., Molteni, R., & V. Edgerton. (2002). Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J Neurophysiol. 88(5): 2187-95.
This article is easy to understand and it describes the effect of exercise on brain health and plasticity.
3. Vaynman, S., Ying, Z., & F. Gomez-Pinilla. (2003). Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity. Neuroscience 122(3): 647-57.
This article is fairly easy to read and it discusses the possible mechanisms through which exercise may influence levels of BDNF.
4. Simmons DA, Mehta RA, Lauterborn JC, Gall CM, Lynch G. Brief ampakine treatments slow the progression of Huntington’s disease phenotypes in R6/2 mice. Neurobiol Dis. 2011 Feb;41(2):436-44.
A technical article that describes how ampakines raise BDNF levels in HD mice
5. Zuccato C. et al. (2001) Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science, 293, 493-496.
This is a technical article that describes how the beneficial activity of huntingtin is lost in people with HD and how this leads to decreased production of BDNF.
6. Zuccato C., Tartari T., Crotti C., Goffredo D., Valenza M., Conti L., Cataudella T., Leavitt B. R., Hayden M. R.,Timmusk T., Rigamonti D. & Cattaneo E. (2003) Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nature Genetics 35: 76-83.
This article is very technical. It describes in detail how normal huntingtin increases transcription of BDNF by silencing NSRE.


D. McGee, 1-1-06, Updated by M. Hedlin 9.27.11 More