Chronic Inhibition of FAAH Reduces Depressive-Like Behavior and Improves Dentate Gyrus Proliferation after Chronic Unpredictable Stress Exposure.

Symptoms of depressive disorders such as anhedonia and despair can be a product of an aberrant adaptation to stress conditions. Chronic unpredictable stress model (CUS) can generate an increase in the activity of the hypothalamic-pituitary-adrenal axis (HPA) and induce a reduction of neurotrophin signaling and the proliferation of neural progenitors in the adult dentate gyrus, together with increased oxidative stress. Levels of the endocannabinoid anandamide (AEA) seem to affect these depression-by-stress-related features and could be modulated by fatty acid amide hydrolase (FAAH). We aimed to evaluate the effects of FAAH inhibitor, URB597, on depressive-like behavior and neural proliferation of mice subjected to a model of CUS. URB597 was administered intraperitoneally at a dose of 0.2 mg/kg for 14 days after CUS. Depressive-like behaviors, anhedonia, and despair were evaluated in the splash and forced swimming tests, respectively. Alterations at the HPA axis level were analyzed using the relative weight of adrenal glands and serum corticosterone levels. Oxidative stress and brain-derived neurotrophic factor (BDNF) were also evaluated. Fluorescence immunohistochemistry tests were performed for the immunoreactivity of BrdU and Sox2 colabeling for comparison of neural precursors. The administration of URB597 was able to reverse the depressive-like behavior generated in mice after the model. Likewise, other physiological responses associated with CUS were reduced in the treated group, among them, increase in the relative weight of the adrenal glands, increased oxidative stress, and decreased BDNF and number of neural precursors. Most of these auspicious responses to enzyme inhibitor administration were blocked by employing a cannabinoid receptor antagonist. In conclusion, the chronic inhibition of FAAH generated an antidepressant effect, promoting neural progenitor proliferation and BDNF expression, while reducing adrenal gland weight and oxidative stress in mice under the CUS model.

ß-Caryophyllene exerts protective antioxidant effects through the activation of NQO1 in the MPTP model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder, caused by the selective death of dopaminergic neurons in the substantia nigra pars compacta. ß-caryophyllene (BCP) is a phytocannabinoid with several pharmacological properties, producing anti-inflammatory and antihypertensive effects. In addition, BCP protects dopaminergic neurons from neuronal death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), yet it remains unclear if this effect is due to its antioxidant activity. To assess whether this is the case, the effect of BCP on the expression and activity of NAD(P)H quinone oxidoreductase (NQO1) was evaluated in mice after the administration of MPTP. Male C57BL/6 J mice were divided into four groups, the first of which received saline solution i.p. in equivalent volume and served as a control group. The second group received MPTP. The second group received MPTP hydrochloride (5 mg/kg, i.p.) daily for seven consecutive days. The third group received BCP (10 mg/kg) for seven days, administered orally and finally, the fourth group received MPTP as described above and BCP for 7 days from the fourth day of MPTP administration. The results showed that BCP inhibits oxidative stress-induced cell death of dopaminergic neurons exposed to MPTP at the same time as it enhances the expression and enzymatic activity of NQO1. Also, the BCP treatment ameliorated motor dysfunction and protected the dopaminergic cells of the SNpc from damage induced by MPTP. Hence, BCP appears to achieve at least some of its antioxidant effects by augmenting NQO1 activity, which protects cells from MPTP toxicity. Accordingly, this phytocannabinoid may represent a promising pharmacological option to safeguard dopaminergic neurons and prevent the progression of PD.

Oxidative, Reductive, and Nitrosative Stress Effects on Epigenetics and on Posttranslational Modification of Enzymes in Cardiometabolic Diseases.

Oxidative (OS), reductive (RS), and nitrosative (NSS) stresses produce carbonylation, glycation, glutathionylation, sulfhydration, nitration, and nitrosylation reactions. OS, RS, and NSS are interrelated since RS results from an overactivation of antioxidant systems and NSS is the result of the overactivation of the oxidation of nitric oxide (NO). Here, we discuss the general characteristics of the three types of stress and the way by which the reactions they induce (a) damage the DNA structure causing strand breaks or inducing the formation of 8-oxo-d guanosine; (b) modify histones; (c) modify the activities of the enzymes that determine the establishment of epigenetic cues such as DNA methyl transferases, histone methyl transferases, acetyltransferases, and deacetylases; (d) alter DNA reparation enzymes by posttranslational mechanisms; and (e) regulate the activities of intracellular enzymes participating in metabolic reactions and in signaling pathways through posttranslational modifications. Furthermore, the three types of stress may establish new epigenetic marks through these reactions. The development of cardiometabolic disorders in adult life may be programed since early stages of development by epigenetic cues which may be established or modified by OS, RS, and NSS. Therefore, the three types of stress participate importantly in mediating the impact of the early life environment on later health and heritability. Here, we discuss their impact on cardiometabolic diseases. The epigenetic modifications induced by these stresses depend on union and release of chemical residues on a DNA sequence and/or on amino acid residues in proteins, and therefore, they are reversible and potentially treatable.

Chitosan/copper nanocomposites: Correlation between electrical and antibacterial properties.

Correlation between electrical and antibacterial properties of chitosan/copper nanocomposites (CS/CuNPs) is investigated. We aim at achieving the minimum CuNPs concentration in a CS-matrix while keeping high antibacterial activity. UV-vis, TEM and XRD measurements confirms the formation of polygonal metallic CuNPs (ca. 30-50 nm). Interactions between NH2/OH groups of CS and CuNPs were determined by FTIR and XPS suggesting Cu chelation-induced mechanism during the CuNPs formation. DC electrical conductivity measurements reveals a percolation threshold at CuNPs volumetric concentration of ca. 0.143%. Antibacterial assays against Gram-positive bacteria and DC measurements helps correlate the antibacterial potency to the electron transfer between the negatively charged bacteria and CuNPs. Our study suggests that nanocomposite's maximum antibacterial activity is obtained below the electrical percolation threshold at extremely low CuNPs concentrations; this fact may prove useful in the design of nontoxic nanocomposites for biomedical applications.

Combined antibacterial/tissue regeneration response in thermal burns promoted by functional chitosan/silver nanocomposites.

We report the combined antibacterial/tissue regeneration responses to thermal burns promoted by functional chitosan/silver nanocomposites (CS/nAg) with ultralow silver content (0.018wt.%, 7-30nm). Our approach allows one to produce CS/nAg nanocomposites without silver nanoparticles (nAg) agglomeration, with bactericide potency higher than 1wt.% of nAg (ca. 10nm) content and, promoting the healing process in controlled thermal burns. CS/nAg films exhibit high antibacterial activity against S. aureus and P. aeruginosa after 1.5h of incubation, demonstrating the bacterial penetration into hydrated films and their interaction with nAg. Additionally, exceptional healing of induced thermal burns was obtained by increasing myofibroblasts, collagen remodeling, and blood vessel neoformation. These factors are associated with epiderma regeneration after 7days of treatment with no nAg release. Our results corroborate the controlled synthesis of nAg embedded in CS matrix with combined antibacterial/biocompatibility properties aiming to produce functional nanocomposites with potential use in wound dressing and health care applications.

Effects of bupropion on the ejaculatory response of male rats.

Chronic antidepressant treatment is associated with sexual side effects, particularly affecting the ejaculatory response. Bupropion (BP), an antidepressant inhibiting dopamine/noradrenaline reuptake, seems to have a low impact upon male sexual function. Ejaculation is regulated both at the brain and spinal cord by the spinal generator for ejaculation (SGE). We investigated the effects of chronic BP treatment on ejaculatory behavior and on SGE functioning. Sexually experienced male rats were intraperitoneally (i.p.) injected with BP (7.5 or 15 mg kg(-1)) during 14 days and tested for sexual behavior on days 1, 7 and 14 of treatment; these same males were used to evaluate the functioning of the SGE by recording the genital motor pattern for ejaculation (GMPE). Acute and chronic BP administration did not importantly modify copulatory behavior of male rats. Chronic treatment with the low dose of BP produced deficits in the functioning of the SGE that were restored by activation of the SGE through afferent stimulation. Conversely, chronic treatment with the high-dose of BP disrupted the functioning of the SGE, as the deficits were not compensated by activating the SGE through sensory stimulation. It is concluded that chronic BP at high doses alters the functioning of the SGE.

HIF-1α expression in the hippocampus and peripheral macrophages after glutamate-induced excitotoxicity.

Hypoxia-inducible factor-1 alpha (HIF-1α) is a master transcription factor that regulates the response to hypoxia and ischemia and induces the expression of various genes, including vascular endothelial growth factor (VEGF) and erythropoietin (EPO). This study shows the systemic response of increased HIF-1α, EPO, and VEGF mRNA and protein. In addition, VEGF expression was increased in neurons and over-expressed in glial cells in a model of neuroexcitotoxicity in the hippocampus, in which rats were neonatally exposed to high glutamate concentrations. Simultaneous increases in HIF-1α, EPO and VEGF mRNA in peritoneal macrophages were also observed. Our study is consistent with the hypothesis that these genes exert a protective effect in response to neurotoxicity.

Expression of HIF-1 alpha, VEGF and EPO in peripheral blood from patients with two cardiac abnormalities associated with hypoxia.

OBJECTIVES: HIF-1 alpha (hypoxia-inducible factor-1 alpha) mediates the responses of mammalian cells to hypoxia/ischemia by inducing the expression of adaptive gene products (e.g., vascular endothelial growth factor (VEGF) and erythropoietin (EPO)). Persistent pulmonary hypertension of the newborn (PPHN) and cyanotic congenital heart disease (CCHD) are common neonatal diseases considered as paradigms of hypoxemia. Since the expression HIF-1 alpha, VEGF and EPO in newborns diagnosed with these diseases has yet to be studied, we set out to define the expression of these genes in peripheral blood from newborn infants diagnosed with PPHN and CCHD. DESIGN AND METHODS: The mRNA transcripts encoding HIF-1 alpha, VEGF and EPO were measured by RT-PCR in healthy newborn infants and infants diagnosed with PPHN and CCHD. RESULTS: An important increase in HIF-1 alpha expression was observed in both pathological conditions, accompanied by significant increases in VEGF and EPO expression when compared to healthy infants. CONCLUSIONS: HIF-1 alpha mRNA expression increases in newborn infants with PPHN or CCHD, as does the expression of its target genes VEGF and EPO.

Changes in hippocampal NMDA-R subunit composition induced by exposure of neonatal rats to L-glutamate.

Overactivation of NMDA-Rs may mediate excitotoxic cell death associated with epileptic seizures, and hypoxic-ischemic conditions. We assessed whether repeated subcutaneous administration of l-glutamate to neonatal rats affects the subunit composition of NMDA-Rs. Accordingly, cortical and hippocampal tissue from 14-day-old rats was analyzed by Western blotting and RT-PCR to quantify the protein and mRNA expression of different NMDA-R subunits. In addition, tissue sections were Nissl stained to assess the cell damage in this tissue. Early exposure of neonatal rats to L-glutamate differentially affects the expression of mRNA transcripts for NMDA-R subunits in the cerebral cortex and hippocampus. In the cerebral cortex, a decrease in NR2B subunit mRNA expression was observed, as well as a loss of NR1 and NR2A protein. By contrast, neonatal L-glutamate administration augmented the transcripts encoding the NR1, NR2B, and NR2C subunits in the hippocampal formation. The expression of mRNA encoding the NR2A subunit was not affected by neonatal L-glutamate administration in either of the brain regions examined. This differential expression of NMDA-R subunits following neonatal exposure to L-glutamate may represent an adaptive response of the glutamate receptors to overactivation in order to reduce the effect of high L-glutamate during the early period of life when the animal is more vulnerable to excitotoxicity.

Cytological damage of nasal epithelium associated with decreased glutathione peroxidase in residents from a heavily polluted city.

OBJECTIVE: To evaluate the cytological damage and glutathione peroxidase (GPX) content in the nasal epithelium of residents of Southwest Metropolitan Mexico City (SWMMC) along 1 year of ozone and PM(10) exposure. METHOD: Four nasal scrapings were obtained in 20 volunteers from a control low polluted city and SWMMC permanent residents (n = 20) during 1 year. The scrapings were obtained in September and December 2004, and February and May 2005. One part of the scraping was stained by hematoxylin-eosin technique for cytological evaluation and a second part was stained by immunocytochemistry method to evaluate GPX concentration by morphometry. RESULTS: Control subjects: in total, 30% had no cytological alterations and 70% showed only mild or moderate inflammation in four nasal scrapings. All SWMMC residents showed moderate to severe inflammatory processes in some scrapings. Additionally, dysplasia was found once (in 2 cases) or more than on scraping in five cases (25%). GPX concentration in the control group remained highest in median values throughout the study. SWMMC residents with the highest median values of GPX content were found in the May and September scrapings, and the lowest median values were found in December and February when Ozone and PM(10) levels are increased (P < or = 0.05). A lower GPX content was found as the cytological damage increased (P < or = 0.001). CONCLUSION: Cytological evaluation of nasal epithelium and GPX immunodetection are satisfactory methods to evaluate the earliest damage produced by atmospheric pollution in heavily contaminated cities.

Takayasu arteritis: clinical features in 110 Mexican Mestizo patients and cardiovascular impact on survival and prognosis.

OBJECTIVE: Takayasu Arteritis (TA) is a rare disease that mainly affects large elastic arteries. It is more frequently seen in Asia, the Mediterranean basin, South Africa and Latin America. We have characterized its clinical manifestations and identified the cardiovascular mortality predictors in a cohort of 110 Mexican Mestizo patients. MATERIAL AND METHOD: Retrospective review of 110 charts of TA patients complying with the American College of Rheumatology (ACR) criteria, seen in a single hospital between 1976 and 2003. Demographic, clinical, and radiological characteristics were described. With the use of actuarial table analysis at 2, 5, and 10 years, and Kaplan Meier methods applying t function for probability, plus Cox regression analysis, the following factors were identified as mortality predictors: systemic arterial hypertension, coronary heart disease and aortic valve regurgitation. Informed consent and approval from the institutional Internal Review Board (IRB) were obtained. RESULTS: We observed a slowly progressive widespread obstructive arterial disease with cardiovascular (48%), neuro-ophthalmic (36%), and skin morbidity (13%). Systemic hypertension and heart disease were significant mortality predictors. Twenty-six percent of cases died due to myocardial infarction, chronic renal failure, stroke, or surgical complications. CONCLUSION: TA in Mexican Mestizos shows a clinical pattern similar to the one recognized in the Far East. Management strategies must be directed at reducing the identified mortality risk factors.

Role of p38 MAPK and pro-inflammatory cytokines expression in glutamate-induced neuronal death of neonatal rats.

Pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6 rises significantly during neuronal damage and activate the signaling p38 MAPK pathway, which is involved in the apoptotic (AP) neuronal death. Systemic administration of glutamate as monosodium salt (MSG) to newborn animals induces neuronal death, however whether neurons die by AP or necrosis through MAPK p38 pathway activation it is unknown. In this study, TNF-alpha, IL-1beta and IL-6 expression levels, AP neuronal death and cellular type that produces TNF-alpha was also identified in the cerebral cortex (CC) and striatum (St) of rats at 8, 10, and 14 days of age after neonatal exposure to MSG. TNF-alpha production and AP neuronal death was significantly increased in the CC at PD8-10, and in the St in all ages studied by excitotoxicity effect induced with MSG. This effect was completely inhibited by SB203580 (p38 inhibitor) in both regions studied. TNF-alpha, IL-1beta and IL-6 RNAm increased after MSG administration, whereas SB203580 did not modify their expression. These data indicates that neuronal death induced by excitotoxicity appears to be mediated through p38 signaling pathway activated by TNF-alpha and their inhibition may have an important neuroprotective role as part of anti-inflammatory therapeutic strategy.

Neuronal damage and changes in the expression of muscarinic acetylcholine receptor subtypes in the neonatal rat cerebral cortical upon exposure to sparteine, a quinolizidine alkaloid.

Sparteine is a quinolizidine alkaloid (QA) produced by Lupine species that has generated much interest due to its anti-hypertensive, anti-pyretic, and anti-inflammatory properties. In the nervous system, sparteine has been shown to display anti-cholinergic and depressive activity, although how sparteine exerts its toxic effects in the brain remains unclear. We have addressed this issue by administering subcutaneous injections of sparteine (25 mg/kg of body weight) to rats on postnatal days 1 and 3, and then examining the expression of the muscarinic acetylcholine receptor (mAChR) subunits m1-m4 in the brains of the neonatal rats 14-60 days later. Administration of sparteine to neonatal rats caused neuronal damage in the cerebral motor cortex accompanied by transient changes in the expression of m1-m4 mAChR subunits as revealed by both RT-PCR and Western blotting. This effect could be prevented by pre-treatment with atropine (10 mg/kg) 1 h prior to the injection of sparteine, suggesting that the cytotoxic activity of sparteine is mediated through mAChRs.

Neuronal cell death due to glutamate excitotocity is mediated by p38 activation in the rat cerebral cortex.

Excitotoxic neuronal death occurs through the activation of NMDA and non-NMDA glutamatergic receptors in the CNS. Glutamate also induces strong activation of p38 and indeed, cell death can be prevented by inhibitors of the p38 pathway. Furthermore, intracellular signals generated by AMPA receptors activate the stress sensitive MAP kinases implicated in apoptotic neuronal death, such as JNK and p38. To investigate the relationship between these elements, we have used immunohistochemistry to analyze the expression of GluR2 in the cerebral cortex of postnatal rats (postnatal Day [PD] 8 and 14) after administering them with monosodium glutamate (MSG; 4 mg/g body weight on PD1, 3, 5, and 7). Similarly, the expression of REST, Fas-L and Bcl-2 mRNA transcripts in animals exposed to a p38 inhibitor, SB203580 (0.42 microg/g body weight, administered subcutaneously) was determined by reverse transcriptase-PCR. The enhanced GluR2-expression in the cerebral cortex at PD8 and the down regulation of this receptor at PD14 was correlated with neuronal damage induced by excitotoxicity. In addition, the enhanced expression of REST at PD8 and PD14 suggests that the induction of REST transcription contributes to glutamate-induced excitotoxic neurodegeneration, possibly by modulating GluR2 expression. Fas-L and Bcl-2 over expression at PD8 and their subsequent down regulation at PD14 also suggests that Fas-L could be the direct effector of apoptosis in the cerebral cortex. On the other hand, the presence of Bcl-2 at PD8 could attenuate certain survival signals in neurons under these neurotoxic conditions. Thus, a change in glutamate receptor composition, and enhanced Fas-L and Bcl-2 expression, coupled with activation of the p38/SAPK pathway appear to be events involved in the neuronal apoptosis induced under neurotoxic conditions.

NR1, NR2A and NR2C subunits expression after cervical spinal cord transplant and section in dogs.

This paper served to evaluate the expression levels of subunits NR1, NR2A and NR2C which are implicated in neuronal plasticity events. A 50% (right half) 4 mm longitudinal resection of the spinal cord was done at the C5-C6 level with preservation of the anterior spinal artery. This was effected in a dog model after either a homologous transplant or a pure spinal cord section. In this study we used two groups of dogs with four individuals each, as well as a control group. The transplant group (n=4) was analyzed at days 3 and 28 post surgery. The section group (n=4) was also analyzed at days 3 and 28 post op. All three groups (transplant, section and control) were evaluated as to the subunit expression in each of the segments corresponding to the transplanted or sectioned sites, the site contralateral to the transplanted or sectioned sites at levels half a centimeter both proximal and distal to the site of transplant and section. The results showed a variety of changes in each of the subunits depending on the group, the segment and the time of evaluation (acute versus chronic). This could be closely related to mechanisms which participate in regeneration and functional recuperation.

Gender impact in systemic lupus erythematosus.

OBJECTIVE: Systemic Lupus Erythematousus (SLE), an autoimmune disease of unknown etiology manifesting as a pleomorphic systemic disease, affects mostly females, (female:male ratio 9:1). Clinical differences between genders, including a higher death rate in males, has been reported. Here we compared clinical manifestations and the 5-year survival probability in Mexican male and female crossbred cases living under similar socioeconomic conditions. A systematic review of published literature was also carried out. MATERIAL AND METHODS: SLE patients treated at the Instituto Nacional de Cardiología "Ignacio Chávez" México City who fulfilled at least four classification criteria (ACR) were included. The frequency of clinical variables with emphasis on cardiovascular findings before and after the diagnosis were described, disease activity based on a validated scale (SLEDAI) was determined, and the 5-year survival rate was estimated. RESULTS: There were 33 men and 158 women, average age of 31 in both groups ranging from 7 to 65 and from 10 to 75 year in male and female patients respectively; both groups were followed for 3.8 years (median), average activity was of 12 points with a range of 5 to 23 in men, and 11 with a range of 2 to 24 in women. Main clinical characteristics in men were: discoid lupus, psychosis, pericarditis, lymphopenia, thrombocytopenia and SLE kidney disease. Immunological tests showed gender-linked differences in regard auto-antibodies (U1-nRNP, Sm, anticardiolipine and false VDRL) and hypocomplementemia. Cardiovascular features and survival rate were not different between gender. CONCLUSION: Male Mexican SLE patients share clinical findings with other male SLE cases reported everywhere as can be deducted from systematic literature review covering 25-year.

NMDAR-2C and 2D subunits gene expression is induced in brain by neonatal exposure of monosodium L-glutamate to adult rats.

Monosodium glutamate (MSG) was administered subcutaneously to male neonate rats, and the effects on N-methyl-D-asparatate (NMDA) subunit receptor types NR2C and NR2D from different brain regions were studied. A semi-quantitative reverse transcription-polymerase chain reaction was used to measure NR2C and NR2D expression levels in the cerebral cortex, hippocampus and striatum. MSG treatment (4 mg/g body weight, on postnatal days 1, 3, 5, and 7) produced an important increase of NR2C and NR2D subunit gene expression levels in the hippocampus and striatum of adults rats. No change was observed in the cerebral cortex. We propose that an early excessive activation of glutamate receptors could modify NMDA subunit expression and its structural composition on postnatal development. This, as part of a compensatory response by an altered neuronal circuitry, mainly in the hippocampus and striatum, suggests that the NMDA receptor could be a determinant factor to modulate the dendritic arrangement and the synaptogenesis.

Immunogenetics and clinical aspects of Takayasu's arteritis patients in a Mexican Mestizo population.

OBJECTIVE: The aim of the present work was to study the association between HLA alleles and Takayasu's arteritis in Mexican Mestizo patients. METHODS: The study included 26 Mexican Mestizo patients with Takayasu's arteritis and 99 healthy unrelated individuals. HLA-A, -B and -DR alleles were determined by polymerase chain reaction PCR-SSP RESULTS: Increased gene frequencies were demonstrated for HLA-B15(p=0.009,pC=0.020,OR=3.24,EF=11.9%) and HLA-B52 (p=0.008, pC=0.027, OR=5.16, EF=7.7%), and a decreased frequency for the HLA-A24 allele in patients compared to normal controls (p=0.035, pC=NS, PF=11.1%). When HLA typing was correlated to clinicalfeatures in 24 cases, wefound an increasedfrequencies of HLA-DR14 in patients with systemic arterial hypertension (p=0.005, pC=0.004, OR=24.6, EF=38.3%) and HLA-A2 on patients with pulmonary involvement (p=0.034, pC=0.036, OR=3.67, EF=40.4%) when compared to patients without these clinical manifestations. CONCLUSION: These data confirm HLA-B52 as a relevant susceptibility allele for Takayasu's arteritis and suggest that HLA-B15 could be important as a marker of the disease in Mexican patients. Other class I and/or class II alleles could also be relevant as markers for the clinical features present in these patients.

Circadian studies of autonomic nervous balance in patients with fibromyalgia: a heart rate variability analysis.

OBJECTIVE: To determine the accumulated 24-hour cardiovascular autonomic modulation and its circadian variations in patients with fibromyalgia, by means of heart rate variability analysis. METHODS: Thirty patients with fibromyalgia and 30 age- and sex-matched controls were studied prospectively. Assessments included a 24-hour ambulatory recording of heart rate variability, time-domain analysis of the accumulated 24-hour R-R interval variations, and power spectral analysis to determine the sympatho/ vagal balance at different hours (calculated as the power spectral density of the low-frequency [0.04-0.15-Hz] sympathetic band divided by the power of the high-frequency [0.15-0.50-Hz] parasympathetic band). RESULTS: Fibromyalgia patients had diminished accumulated 24-hour heart rate variability, manifested by a decreased standard deviation of all R-R intervals (mean +/- SD 126 +/- 35 ms, versus 150 +/- 33 ms in controls; P = 0.008) and a decreased ratio of pairs of adjacent R-R intervals differing by >50 ms (mean +/- SD 12.0 +/- 9.0% versus 20.1 +/- 18.0%; P = 0.031). Patients lost the circadian variations of sympatho/vagal balance, with nocturnal values significantly higher than those of controls at time 0 (mean +/- SD 3.5 +/- 3.2 versus 1.2 +/- 1.0; P = 0.027) and at 3 hours (3.3 +/- 3.0 versus 1.6 +/- 1.4; P = 0.01). CONCLUSION: Individuals with fibromyalgia have diminished 24-hour heart rate variability due to an increased nocturnal predominance of the low-frequency band oscillations consistent with an exaggerated sympathetic modulation of the sinus node. This abnormal chronobiology could explain the sleep disturbances and fatigue that occur in this syndrome. Spectral analysis of heart rate variability may be a useful test to identify fibromyalgia patients who have dysautonomia.