QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Aracava, Y. Articles by Albuquerque, E. X. Search for Related Content PubMed Articles by Aracava, Y. Articles by Albuquerque, E. X.

LETTERS TO THE EDITOR

Response: Comments on "Memantine Blocks 7* Nicotinic Acetylcholine Receptors More Potently Than N-Methyl-D-aspartate Receptors in Rat Hippocampal Neurons"

Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland (Y.A., E.F.R.P., A.M., E.X.A.); and Institute of Physiological Biochemistry and Pathobiochemistry, Johannes Gutenberg-University Medical School, Mainz, Germany (A.M.)

Received January 2, 2005; accepted January 13, 2005.

The pathophysiology of AD is very complex and involves alteration of the amyloid precursor protein (APP) processing, excessive deposits of aggregates, excitotoxicity, and significant alterations in numerous neurotransmitter systems in the brain. Although the cause of AD remains undetermined, one of the most significant neuropathological hallmarks of the disease is the early development of nicotinic cholinergic deficits in the brain. Based on this knowledge, treatments presently approved by the Food and Drug Administration (FDA) for patients with mild-to-moderate AD include the cholinesterase inhibitors donepezil and rivastigmine, as well as galantamine, a drug that acts as a weak cholinesterase inhibitor and a nicotinic allosteric potentiating ligand (Doody, 2003). The N-methyl-D-aspartate (NMDA) receptor antagonist memantine is the only FDA-approved treatment for patients with moderate-to-severe AD (Reisberg et al., 2003). The ability of memantine to improve cognition in these patients seems to result from a selective inhibition of the excessive tonic NMDA receptor activity that accounts for the neurodegeneration observed in AD.

In their comments, Banerjee et al. indicate that recent clinical studies have demonstrated beneficial effects of memantine in patients with mild-to-moderate AD. The clinical data from Peskind et al., which have been presented only in the format of research posters at the 17th Meeting of the American Association for Geriatric Psychiatry (Baltimore, MD; February 21–24, 2004) and the XXIV Collegium Internationale Neuro-Psychopharmacologicum Congress (Paris, France; June 20–24, 2004), has been recently reviewed in Areosa et al. (2004). Peskind et al. enrolled approximately 400 patients that had been diagnosed with mild-to-moderate AD and assigned these patients to treatment with memantine (20 mg/day) or placebo. At the end of the 24-week treatment, patients receiving memantine showed no significant improvements in the activities of daily living. Memantine caused an apparent small, albeit significant improvement in cognition, behavior, and mood, and the outcome of the clinician's interview-based impression of change-plus caregiver input also favored memantine. However, the Cochrane Database Systematic Review of "Memantine on Dementia" reports the existence of two finished but unpublished clinical trials in which memantine failed to improve cognitive or global measures in patients with mild-to-moderate AD. Thus, at this point, we feel that the effects of memantine on mild-to-moderate AD patients are unknown at best. Nevertheless, it has been reported that, based in part on results from Peskind et al., Forest Laboratories, Inc. intended to file a Supplemental New Drug Application with the FDA for approval of memantine for treatment of patients with mild-to-moderate AD (Rosack, 2004). These clinical findings and the presently available preclinical data on the inhibitory actions of memantine in the nicotinic cholinergic system in the brain (Buisson and Bertrand, 1998; Maskell et al., 2003; Aracava et al., 2005) suggest that the prospect of using this drug for treatment of mild-to-moderate AD should be examined with a great deal of awareness and caution.

Although the authors state in their comments that 7 nAChR expression is relatively unaffected in AD regardless of the disease, there are plentiful reports of region-specific losses of 7 nAChRs in the AD brain (Banerjee et al., 2000; Perry et al., 2000; Court et al., 2001; Nordberg, 2001). In fact, the loss of 7 nAChRs is largely pronounced in the hippocampus of AD patients and not as significant in the cerebral cortex (Hellström-Lindahl et al., 1999; Wevers et al., 1999). It is also noteworthy that the degree of losses of cholinergic neurons and nAChRs (particularly 7 and 42) correlate well with the magnitude of cognitive decline in AD patients as the disease progresses from mild to moderate (Francis et al., 1985; Perry et al., 2000; Nordberg, 2001). In patients with more advanced stages of AD, such a correlation between nAChR loss and cognitive impairment does not seem to exist (Sabbagh et al., 2001). These findings support the clinical reports that nicotinic cholinergic enhancing therapies are more effective in patients with mild-to-moderate AD than in patients with moderate-to-severe AD (see Doody, 2003).

There have been several reports that 7 nAChR agonists facilitate induction of long-term potentiation (LTP), a cellular mechanism believed to underlie learning and memory (Hunter et al., 1994; Fujii et al., 2000; Ji et al., 2001; He et al., 2003; Mann and Greenfield, 2003; Matsuyama and Matsumoto, 2003). This effect results from the interactions of the nicotinic agonists with nAChRs, because it can be blocked by nicotinic antagonists, including 1) the 7 nAChR-selective antagonist -bungarotoxin (-BGT) (Hunter et al., 1994); 2) methyllycacotine (MLA) (Ji et al., 2001; Mann and Greenfield, 2003), an alkaloid that inhibits the activity of nAChRs containing 7, 6, and/or 3 subunits (Mogg et al., 2002); and 3) the nonselective nAChR antagonist mecamylamine (Fujii et al., 2000). Addressing the question as to whether facilitation of LTP by nicotinic agonists depends on agonist-induced receptor activation or inactivation became especially relevant for understanding the role of 7 nAChRs in regulation of synaptic plasticity, because these receptors are exquisitely sensitive to agonist-induced desensitization (see Mike et al., 2000 and references therein).

Based on the observation that nicotine-induced facilitation of LTP induction in the CA1 field of hippocampal slices could be mimicked by a high concentration of MLA (100 nM), Fujii et al. (2000) suggested that the effect of nicotine on LTP resulted primarily from agonist-induced 7 nAChR desensitization. A subsequent study performed a quantitative comparative analysis of the effects of nicotine, choline, and -BGT on induction of LTP in the CA1 field of the hippocampus (Mann and Greenfield, 2003). In agreement with the findings reported by Fujii et al. (2000), the nAChR agonists nicotine and choline facilitated induction of LTP (Mann and Greenfield, 2003). Of interest, however, the effect of 1 mM choline on LTP induction was smaller in magnitude than that of 10 mM choline. It is well documented that 1 mM choline is sufficient to fully desensitize 7 nAChRs whereas 10 mM choline is needed to cause nearly full activation of these receptors (see Mike et al., 2000 and references therein). Furthermore, Mann and Greenfield (2003) reported that the effect of -BGT on LTP induction was significantly smaller than that of choline or nicotine. Thus, desensitization explains only in part the facilitation of LTP induction by 7 nAChR agonists; receptor activation is an important determinant of the effect that these drugs have on synaptic plasticity in the hippocampus (Mann and Greenfield, 2003). These findings support the notion that 7 nAChR inhibition underlies the cognitive impairment caused by 7 nAChR antagonists, whereas 7 nAChR activation accounts for the memory-enhancing properties of 7 nAChR agonists in mammals (see Levin, 2002 and references therein).

Equally important were studies designed to investigate the mechanisms by which nicotine and 7 nAChR-selective agonists protect neurons in primary and organotypic cultures against degeneration triggered by different insults (Carlson et al., 1998; Ferchmin et al., 2003; Gahring et al., 2003; see also Dajas-Bailador and Wonnacott, 2004 and references therein). It seems that agonist-induced 7 nAChR desensitization is a determinant of the ability that nicotine and 7 nAChR agonists have to reduce early excitotoxic damage of hippocampal neurons in vitro (Ferchmin et al., 2003). In contrast, agonist-induced 7 nAChR activation is unquestionably essential for the neuroprotective effect that nicotinic agonists have in delayed neurotoxicity (see references above). Ca²⁺ entry and mobilization following 7 nAChR activation in neurons is critical for activation of signaling cascades that can prevent delayed neurodegeneration (reviewed in Dajas-Bailador and Wonnacott, 2004), which resembles the slowly evolving neuronal death occurring in AD and other neurode-generative disorders (see Beal, 1996).

In their letter, the authors make reference to recent studies that have suggested that 7 nAChR activation may contribute to AD pathophysiology and neuropathology. Wang et al. (2003) have reported that the amyloid peptide A1-42, via specific interactions with 7 nAChRs, induces phosphorylation of the protein. It should be noted, however, that in that study A1-42-induced phosphorylation was blocked by concentrations of -BGT and MLA that are 1,000-fold higher than those needed to block ion flux through 7 nAChRs and was insensitive to blockade by the nonselective nAChR antagonist mecamylamine (Wang et al., 2003). Thus, it is unlikely that phosphorylation resulted from the activation of 7 nAChRs by A1-42. The work of Dineley et al. (2001, 2002) provided evidence that in the hippocampus of transgenic mice, high levels of A1-42 lead to increased expression of 7 nAChRs and that A1-42, acting most likely as an 7 nAChR agonist, causes chronic activation and subsequently down-regulation of the extracellular signal-regulated-protein kinase. These results led to the hypothesis that 7 nAChR-mediated alterations in extracellular signal-regulated-protein kinase activity could be one of the mechanisms underlying the disruption of synaptic functions and plasticity and, ultimately, the cognitive impairment observed in AD (Dineley et al., 2001, 2002). Unfortunately, these findings and hypotheses resulted from experiments carried out using transgenic mouse lines that express a mutant human presenilin-1 (PS-1), a mutant human APP, or both mutant human PS-1/APP. As such, it is unclear whether they can be used to interpret the neuropathology of AD, because these animal models do not reproduce the neuropathology of this catastrophic disease (Dodart et al., 2002; Higgins and Jacobsen, 2003). In particular, expression of 7 nAChRs is known to be increased in the hippocampi of the APP and PS-1/APP mice, whereas levels of these receptors are known to be decreased in the hippocampi of AD patients. In addition, one of the hallmarks of AD, the large loss of brain cholinergic neurons, is absent in the brain of these transgenic mice (Hernandez et al., 2001). Finally, the APP and PS-1/APP mice both lack the pathology associated with AD (Higgins and Jacobsen, 2003).

Although the possible effects of memantine on the eye-blink conditioning response in AD patients are hitherto unknown, it has been demonstrated that the nicotinic cholinergic system plays a central role in modulating this form of associative learning that is impaired in Alzheimer's disease (Woodruff-Pak, 2001). The classic eye-blink conditioning response is improved by nicotine and 7 nAChR agonists (Leon-S et al., 1997; Woodruff-Pak et al., 2000) and impaired by nAChR antagonists (Woodruff-Pak, 2003). Therefore, it is troublesome that a single 30-mg dose of memantine can cause impairment of this response in young health subjects (Schugens et al., 1997).

The clinical relevance of the finding that memantine reduces the accuracy and rate of response of rats in a fixed consecutive number task (Willmore et al., 2001) has been questioned by Banerjee et al. In general, a decreased performance in fixed consecutive number tasks is indicative of disruption of working memory (Sanger, 1992). However, as the authors pointed out in their comments, the reduction of accuracy by memantine cannot be unambiguously attributed to memory impairment, because at the doses that memantine reduced response accuracy, it also decreased response rates (Willmore et al., 2001). Nevertheless, memantine decreased task accuracy with ED₅₀ values ranging from 4.2 to 12.0 mg/kg (Willmore et al., 2001); these doses are significantly lower than those used experimentally to ameliorate memory impairment induced by excessive glutamatergic activation in rats (Misztal et al., 1996) and those recommended clinically for AD treatment (Reisberg et al., 2003). Identifying the doses at which memantine selectively decreases response accuracy in this test would probably depend on increasing the complexity of the task (Willmore, 2003). A more recent study demonstrated that 10 mg/kg memantine impairs retention of a reference memory-based spatial learning task (Creeley et al., 2004). Therefore, it seems that memantine improves cognitive processing impaired by excessive glutamatergic activity and impairs cognition under conditions in which glutamatergic activity is not overtly increased.

In closing, we would like to emphasize that different research groups have consistently demonstrated that losses of cholinergic neurons and nAChRs, particularly 7 and 42, correlate well with the cognitive decline in AD at early stages. There is also plentiful evidence that 7 nAChR activation is neuroprotective and improves memory, whereas 7 nAChR inhibition impairs memory. Thus, it can be concluded that should inhibition of 7 nAChRs by memantine take place in the human brain, it would decrease the effectiveness of the drug in the treatment of patients with mild-to-moderate AD, although being of no great significance in patients with moderate-to-severe AD, when apparently the degree of loss of nAChRs no longer correlates with the cognitive decline of the patients (Sabbagh et al., 2001). Our findings strongly substantiate the need of further preclinical studies to address the benefits of using memantine for the treatment of patients with mild-to-moderate AD. As of today, the results of the clinical trials of memantine on these patients have certainly been rather disappointing. In the 24-week trials, memantine has either been ineffective or only slightly effective in improving the overall conditions of patients with mild-to-moderate AD (reviewed in Areosa et al., 2004).

	Footnotes

 
doi:10.1124/jpet.104.082222.

ABBREVIATIONS: AD, Alzheimer's disease; APP, amyloid precursor protein; FDA, Food and Drug Administration; NMDA, N-methyl-D-aspartate; nAChR, nicotinic acetylcholine receptor; LTP, long-term potentiation; BGT, bungarotoxin; MLA, methyllycacotine; PS, presenilin.

	References

Top References

 

Aracava Y, Pereira EFR, Maelicke A, and Albuquerque EX (2005) Memantine blocks 7* nicotinic acetylcholine receptors more potently than N-methyl-D-aspartate receptors in rat hippocampal neurons. J Pharm Exp Ther 313: 1195–1205

Areosa SA, McShane R, and Sherriff F (2004) Memantine for dementia. Cochrane Database Syst Rev 4: CD003154.

Banerjee C, Nyengaard JR, Wevers A, de Vos RA, Jansen Steur EN, Lindstrom J, Pilz K, Nowacki S, Bloch W, and Schröder H (2000) Cellular expression of 7 nicotinic acetylcholine receptor protein in the temporal cortex in Alzheimer's and Parkinson's disease—a stereological approach. Neurobiol Dis 7: 666–672.[CrossRef][Medline]

Beal MF (1996) Mitochondria, free radicals and neurodegeneration. Curr Opin Neurobiol 6: 661–666.[CrossRef][Medline]

Buisson B and Bertrand D (1998) Open-channel blockers at the human 42 neuronal nicotinic acetylcholine receptor. Mol Pharmacol 53: 555–563.[Abstract/Free Full Text]

Carlson NG, Bacchi A, Rogers SW, and Gahring LC (1998) Nicotine blocks TNF-alpha-mediated neuroprotection to NMDA by an alpha-bungarotoxin-sensitive pathway. J Neurobiol 35: 29–36.[CrossRef][Medline]

Court J, Martin-Ruiz C, Piggott M, Spurden D, Griffiths M, and Perry E (2001) Nicotinic receptor abnormalities in Alzheimer's disease. Biol Psychiatry 49: 175–184.[CrossRef][Medline]

Creeley CE, Olney JW, Taylor GT, and Wozniak DF (2004) Memantine impairs retention of a spatial learning task at low doses in adult rats. Society for Neuroscience program number 219.5.

Dajas-Bailador F and Wonnacott S (2004) Nicotinic acetylcholine receptors and the regulation of neuronal signaling. Trends Pharmacol Sci 25: 317–324.[CrossRef][Medline]

Dineley KT, Westerman M, Bui D, Bell K, Ashe KH, and Sweatt JD (2001) -Amyloid activates the mitogen-activated protein kinase cascade via hippocampal 7 nicotinic acetylcholine receptors: In vitro and in vivo mechanisms related to Alzheimer's disease. J Neurosci 21: 4125–4133.[Abstract/Free Full Text]

Dineley KT, Xia X, Bui D, Sweatt JD, and Zheng H (2002) Accelerated plaque accumulation, associative learning deficits and up-regulation of 7 nicotinic receptor protein in transgenic mice co-expressing mutant human presenilin 1 and amyloid precursor proteins. J Biol Chem 277: 22768–22780.[Abstract/Free Full Text]

Dodart JC, Mathis C, Bales KR, and Paul SM (2002) Does my mouse have Alzheimer's disease? Genes Brain Behav 1: 142–155.[CrossRef][Medline]

Doody RS (2003) Current treatments for Alzheimer's disease: cholinesterase inhibitors. J Clin Psychiatry 64: 11–17.

Ferchmin PA, Perez D, Eterovic VA, and de Vellis J (2003) Nicotinic receptors differentially regulate N-methyl-D-aspartate damage in acute hippocampal slices. J Pharmacol Exp Ther 305: 1071–1078.[Abstract/Free Full Text]

Francis PT, Palmer AM, Sims NR, Bowen DM, Davison AN, Esiri MM, Neary D, Snowden JS, and Wilcock GK (1985) Neurochemical studies of early-onset Alzheimer's disease. Possible influence on treatment. N Engl J Med 313: 7–11.[Abstract]

Fujii S, Ji Z, and Sumikawa K (2000) Inactivation of 7 ACh receptors and activation of non-7 ACh receptors both contribute to long term potentiation induction in the hippocampal CA1 region. Neurosci Lett 286: 134–138.[CrossRef][Medline]

Gahring LC, Meyer EL, and Rogers SW (2003) Nicotine-induced neuroprotection against N-methyl-D-aspartic acid or -amyloid peptide occur through independent mechanisms distinguished by pro-inflammatory cytokines. J Neurochem 87: 1125–1136.[CrossRef][Medline]

He J, Deng CY, Zhu XN, Yu JP, and Chen RZ (2003) Different synaptic mechanisms of long-term potentiation induced by nicotine and tetanic stimulation in hippocampal CA1 region of rats. Acta Pharmacol Sin 24: 398–402.[Medline]

Hellström-Lindahl E, Mousavi M, Zhang X, Ravid R, and Nordberg A (1999) Regional distribution of nicotinic receptor subunit mRNAs in human brain: comparison between Alzheimer and normal brain. Brain Res Mol Brain Res 66: 94–103.[Medline]

Hernandez D, Sugaya K, Qu T, McGowan E, Duff K, and McKinney M (2001) Survival and plasticity of basal forebrain cholinergic systems in mice transgenic for presenilin-1 and amyloid precursor protein mutant genes. Neuroreport 12: 1377–1384.[CrossRef][Medline]

Higgins GA and Jacobsen H (2003) Transgenic mouse models of Alzheimer's disease: phenotype and application. Behav Pharmacol 14: 419–438.[Medline]

Hunter BE, de Fiebre CM, Papke RL, Kem WR, and Meyer EM (1994) A novel nicotinic agonist facilitates induction of long-term potentiation in the rat hippocampus. Neurosci Lett 168: 130–134.[CrossRef][Medline]

Ji D, Lape R, and Dani JA (2001) Timing and location of nicotinic activity enhances or depresses hippocampal synaptic plasticity. Neuron 31: 131–141.[CrossRef][Medline]

Leon-S FE, Suwazono S, Takenaga S, Arimura K and Osame M (1997) The effects of tobacco smoking on the short, middle and long latency responses of the blink reflex in humans. J Clin Neurophysiol 14: 144–149.[Medline]

Levin ED (2002) Nicotinic receptor subtypes and cognitive function. J Neurobiol 53: 633–640.[CrossRef][Medline]

Mann EO and Greenfield SA (2003) Novel modulatory mechanisms revealed by the sustained application of nicotine in the guinea-pig hippocampus in vitro. J Physiol 551: 539–550.[Abstract/Free Full Text]

Maskell PD, Speder P, Newberry NR, and Bermudez I (2003) Inhibition of human 7 nicotinic acetylcholine receptors by open channel blockers of N-methyl-D-aspartate receptors. Br J Pharmacol 140: 1313–1319.[CrossRef][Medline]

Matsuyama S and Matsumoto A (2003) Epibatidine induces long-term potentiation (LTP) via activation of 42 nicotinic acetylcholine receptors (nAChRs) in vivo in the intact mouse dentate gyrus: both 7 and 42 nAChRs essential to nicotinic LTP. J Pharmacol Sci 93: 180–187.[CrossRef]

Mike A, Castro NG, and Albuquerque EX (2000) Choline and acetylcholine have similar kinetic properties of activation and desensitization on the 7 nicotinic receptors in rat hippocampal neurons. Brain Res 882: 155–168.[CrossRef][Medline]

Misztal M, Frankiewicz T, Parsons CG, and Danysz W (1996) Learning deficits induced by chronic intraventricular infusion of quinolinic acid—protection by MK-801 and memantine. Eur J Pharmacol 296: 1–8.[CrossRef][Medline]

Mogg AJ, Whiteaker P, McIntosh JM, Marks M, Collins AC, and Wonnacott S (2002) Methyllycaconitine is a potent antagonist of -conotoxin-MII-sensitive presynaptic nicotinic acetylcholine receptors in rat striatum. J Pharmacol Exp Ther 302: 197–204.[Abstract/Free Full Text]

Nordberg A (2001) Nicotinic receptor abnormalities of Alzheimer's disease: therapeutic implications. Biol Psychiatry 49: 200–210.[CrossRef][Medline]

Perry E, Martin-Ruiz C, Lee M, Griffiths M, Johnson M, Piggott M, Haroutunian V, Buxbaum JD, Nasland J, Davis K, et al. (2000) Nicotinic receptor subtypes in human brain ageing, Alzheimer and Lewy body diseases. Eur J Pharmacol 393: 215–222.[CrossRef][Medline]

Reisberg B, Doody R, Stöfller A, Schmitt F, Ferris S, and Möbius HJ: Memantine study group (2003) Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 348: 1333–1341.[Abstract/Free Full Text]

Rosack J (2004) Geriatric psychiatrists encouraged by new Alzheimer's drug. Psychiatric News 39: 58–59.[Free Full Text]

Sabbagh MN, Reid RT, Hansen LA, Alford M, and Thal LJ (2001) Correlation of nicotinic receptor binding with clinical and neuropathological changes in Alzheimer's disease and dementia with Lewy bodies. J Neural Transm 108: 1149–1157.

Sanger DJ (1992) NMDA antagonists disrupt timing behaviour in rats. Behav Pharmacol 3: 593–600.[Medline]

Schugens MM, Egerter R, Daum I, Schepelmann K, Klockgether T, and Löschmann P-A (1997) The NMDA antagonist memantine impairs classical eyeblink conditioning in humans. Neurosci Lett 224: 57–60.[CrossRef][Medline]

Wang HY, Li W, Benedetti NJ, and Lee DH (2003) 7 Nicotinic acetylcholine receptors mediate -amyloid peptide-induced tau protein phosphorylation. J Biol Chem 278: 31547–31553.[Abstract/Free Full Text]

Wevers A, Monteggia L, Nowacki S, Bloch W, Schutz U, Lindstrom J, Pereira EFR, Eisenberg H, Giacobini E, de Vos RA, et al. (1999) Expression of nicotinic acetylcholine receptor subunits in the cerebral cortex in Alzheimer's disease: histotopographical correlation with amyloid plaques and hyperphosphorylated-tau protein. Eur J Neurosci 11: 2551–2565.[CrossRef][Medline]

Willmore CB (2003) The cognitive effect profiles of NMDA receptor modulating drugs are resolvable if stimulus complexity is varied in a number discernment task. Behav Cogn Neurosci Rev 2: 130–147.[Abstract]

Willmore CB, Bespalov AY, and Beardsley PM (2001) Competitive and noncompetitive NMDA antagonist effects in rats trained to discriminate lever-press counts. Pharmacol Biochem Behav 69: 493–502.[CrossRef][Medline]

Woodruff-Pak DS (2001) Eyeblink classical conditioning differentiates normal aging from Alzheimer's disease. Integr Physiol Behav Sci 36: 87–108.[Medline]

Woodruff-Pak DS (2003) Mecamylamine reversal by nicotine and by a partial 7 nicotinic acetylcholine receptor agonist (GTS-21) in rabbits tested with delay eyeblink classical conditioning. Behav Brain Res 143: 159–167.[CrossRef][Medline]

Woodruff-Pak DS, Green JT, Coleman-Valencia C, and Pak JT (2000) A nicotinic cholinergic agonist (GTS-21) and eyeblink classical conditioning: acquisition, retention and relearning in older rabbits. Exp Aging Res 26: 323–336.[CrossRef][Medline]

This Article Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Aracava, Y. Articles by Albuquerque, E. X. Search for Related Content PubMed Articles by Aracava, Y. Articles by Albuquerque, E. X.