Renal denervation in an animal model of diabetes and hypertension: Impact on the autonomic nervous system and nephropathy

Background: The effects of renal denervation on cardiovascular reflexes and markers of nephropathy in diabetic-hypertensive rats have not yet been explored. Methods: Aim: To evaluate the effects of renal denervation on nephropathy development mechanisms (blood pressure, cardiovascular autonomic changes, renal GLUT2) in diabetic-hypertensive rats. Forty-one male spontaneously hypertensive rats (SHR) similar to 250 g were injected with STZ or not; 30 days later, surgical renal denervation (RD) or sham procedure was performed; 15 days later, glycemia and albuminuria (ELISA) were evaluated. Catheters were implanted into the femoral artery to evaluate arterial pressure (AP) and heart rate variability (spectral analysis) one day later in conscious animals. Animals were killed, kidneys removed, and cortical renal GLUT2 quantified (Western blotting). Results: Higher glycemia (p < 0.05) and lower mean AP were observed in diabetics vs. nondiabetics (p < 0.05). Heart rate was higher in renal-denervated hypertensive and lower in diabetic-hypertensive rats (384.8 +/- 37, 431.3 +/- 36, 316.2 +/- 5, 363.8 +/- 12 bpm in SHR, RD-SHR, STZ-SHR and RD-STZ-SHR, respectively). Heart rate variability was higher in renal-denervated diabetic-hypertensive rats (55.75 +/- 25.21, 73.40 +/- 53.30, 148.4 +/- 93 in RD-SHR, STZ-SHR-and RD-STZ-SHR, respectively, p < 0.05), as well as the LF component of AP variability (1.62 +/- 0.9, 2.12 +/- 0.9, 7.38 +/- 6.5 in RD-SHR, STZ-SHR and RD-STZ-SHR, respectively, p < 0.05). GLUT2 renal content was higher in all groups vs. SHR. Conclusions: Renal denervation in diabetic-hypertensive rats improved previously reduced heart rate variability. The GLUT2 equally overexpressed by diabetes and renal denervation may represent a maximal derangement effect of each condition.

Exercise training associated with diet improves heart rate recovery and cardiac autonomic nervous system activity in obese children

The purpose of this study was to test the hypotheses that in obese children: 1) hypocaloric diet (D) improves both heart rate recovery at 1 min (Delta HRR1) cfter an exercise test, and cardiac autonomic nervous system activity (CANSA) in obese children; 2) Diet and exercise training (DET) combined leads to greater improvement in both Delta HRR1 after an exercise test and in CANSA, than D alone. Moreover, we examined the relationships among Delta HRR1, CANSA, cardiorespiratory fitness and anthropometric variables (AV) in obese children submitted to D and to DET. 33 obese children (10 +/- 0.2 years; body mass index (BMI) >95(th) percentile) were divided into 2 groups: D (n = 15; BMI = 31 +/- 1 kg/m(2)) and DET (n = 18; 29 +/- 1 kg/m(2)). All children performed a maximal cardiopulmonary exercise test on a treadmill. The Delta HRR1 was defined as the difference between heart rate at peak and at 1-min post-exercise. CANSA was assessed using power spectral analysis of heart rate variability at rest. The sympathovagal balance (low frequency and high frequency ratio, LF/HF) was measured. After interventions, all obese children showed reduced body weight (P < 0.05). The D group did not improve in terms of peak VO(2), Delta HRR1 or LF/HF ratio (P > 0.05). In contrast, the DET group showed increased peak VO(2) (P = 0.01) and improved Delta HRR1 (Delta HRR1 = 37.3 +/- 2.6; P = 0.01) and LF/HF ratio (P = 0.001). The DET group demonstrated significant relationships among Delta HRR1, peak VO(2) and CANSA (P < 0.05). In conclusion, DET, in contrast to D, promoted improved Delta HRR1 and CANSA in obese children, suggesting a positive influence of increased levels of cardiorespiratory fitness by exercise training on cardiac autonomic activity.

Day-night pattern of autonomic nervous system modulation in patients with heart failure with and without sleep apnea

Introduction: Among patients with congestive heart failure (CHF) both obstructive and central sleep apnea (SA) are associated with increased sympathetic activity. However, the day-night pattern of cardiac autonomic nervous system modulation in CHF patients with and without sleep apnea is unknown. Material and methods: Twenty-five CHF patients underwent polysomnography with simultaneous beat-to-beat blood pressure (Portapres), respiration and electrocardiogram monitoring. Patients were divided according to the presence (SA, n=17) and absence of SA (NoSA, n=8). Power spectral analyses of heart rate variability (HRV) and spontaneous baroreflex sensitivity (BRS) were determined in periods with stable breathing while awake at 6 AM, 10 AM, 10 PM, as well as during stage 2 sleep. In addition, muscle sympathetic nerve activity (MSNA) was evaluated at 10 AM. Results: RR variance, low-frequency (LF), high-frequency (HF) powers of HRV, and BRS were significantly lower in patients with SA compared with NoSA in all periods. HF power, a marker of vagal activity, increased during sleep in patients with NoSA but in contrast did not change across the 24-hour period in patients with SA. MSNA was significantly higher in patients with SA compared with NoSA. RR variance, LF and HF powers correlated inversely with simultaneous MSNA (r=-0.64, -0.61, and -0.61 respectively; P < 0.01). Conclusions: Patients with CHF and SA present a reduced and blunted cardiac autonomic modulation across the 24-hour period. These findings may help to explain the increased cardiovascular risk in patients with CHF and SA. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Mutational analysis of genes p14ARF, p15INK4b, p16INK4a, and PTEN in human nervous system tumors

The cancer is one of the most common and severe problems in clinical medicine, and nervous system tumors represent about 2% of the types of cancer. The central role of the nervous system in the maintenance of vital activities and the functional consequences of the loss of neurons can explain how severe brain cancers are. The cell cycle is a highly complex process, with a wide number of regulatory proteins involved, and such proteins can suffer alterations that transform normal cells into malignant ones. The INK4 family members (CDK inhibitors) are the cell cycle regulators that block the progression of the cycle through the R point, causing an arrest in G1 stage. The p14ARF (alternative reading frame) gene is a tumor suppressor that inhibits p53 degradation during the progression of the cell cycle. The PTEN gene is related to the induction of growth suppression through cell cycle arrest, to apoptosis and to the inhibition of cell adhesion and migration. The purpose of the present study was to assess the mutational state of the genes p14ARF, p15INK4b, p16INK4a, and PTEN in 64 human nervous system tumor samples. Homozygous deletions were found in exon 2 of the p15INK4b gene and exon 3 of the p16INK4a gene in two schwannomas. Three samples showed a guanine deletion (63 codon) which led to a loss of heterozygosity in the p15 gene, and no alterations could be seen in the PTEN gene. Although the group of patients was heterogeneous, our results are in accordance with other different studies that indicate that homozygous deletion and loss of heterozygosity in the INK4 family members are frequently observed in nervous system tumors.

Association of Trypanosoma vivax in extracellular sites with central nervous system lesions and changes in cerebrospinal fluid in experimentally infected goats

Changes in cerebrospinal fluid (CSF) and anatomical and histopathological central nervous system (CNS) lesions were evaluated, and the presence of Trypanosoma vivax in CNS tissues was investigated through PCR. Twelve adult male goats were divided into three groups (G): G1, infected with T. vivax and evaluated during the acute phase; G2, infected goats evaluated during the chronic phase; and G3, consisting of non-infected goats. Each goat from G1 and G2 was infected with 1.25 x 10(5) trypomastigotes. Cerebrospinal fluid (CSF) analysis and investigation of T. vivax was performed at the 15(th) day post-infection (dpi) in G1 goats and on the fifth day after the manifestation of nervous system infection signs in G2 goats. All goats were necropsied, and CNS fragments from G1 and G2 goats were evaluated by PCR for the determination of T. vivax. Hyperthermia, anemia and parasitemia were observed from the fifth dpi for G1 and G2, with the highest parasitemia peak between the seventh and 21(st) dpi. Nervous system infection signs were observed in three G2 goats between the 30(th) and 35(th) dpi. CSF analysis revealed the presence of T. vivax for G2. Meningitis and meningoencephalitis were diagnosed in G2. PCR were positive for T. vivax in all the samples tested. In conclusion, T. vivax may reach the nervous tissue resulting in immune response from the host, which is the cause of progressive clinical and pathological manifestations of the CNS in experimentally infected goats.

Gastric Bypass and Cardiac Autonomic Activity: Influence of Gender and Age

Obesity is associated with increased sympathetic activity and higher mortality. Treatment of this condition is often frustrating. Roux-en-Y gastric bypass is the most effective technique nowadays for treatment of obesity. The aim of the present study is to assess the effects of this surgery on the cardiac autonomic activity, including the influence of gender and age, through heart rate variability (HRV) analysis. The study group consisted of 71 obese patients undergoing gastric bypass. Time domain measures of HRV, obtained from 24-h Holter recordings, were evaluated before and 6 months after surgery, and the results were compared. Percentage of interval differences of successive normal sinus beats greater than 50 ms (pNN50) and square root of the mean squared differences of successive normal sinus beat intervals (rMSSD) was used to estimate the short-term components of HRV, related to the parasympathetic activity. Standard deviation of intervals between all normal sinus beats (SDNN) was related to overall HRV. SDNN, pNN50, and rMSSD showed significant increase 6 months after surgery (p < 0.001, p = 0.001 and p = 0.002, respectively). Men presented a greater increase of SDNN than women (p = 0.006) during the follow-up. There was a difference in rMSSD evolution for age groups (p = 0.002). Only younger patients presented significant increase of rMSSD. Overall HRV increased 6 months after surgery; this increase was more evident in men. Cardiac parasympathetic activity increased also, but in younger patients only.

INTENSITY-MODULATED AND 3D-CONFORMAL RADIOTHERAPY FOR WHOLE-VENTRICULAR IRRADIATION AS COMPARED WITH CONVENTIONAL WHOLE-BRAIN IRRADIATION IN THE MANAGEMENT OF LOCALIZED CENTRAL NERVOUS SYSTEM GERM CELL TUMORS

Purpose: To compare the sparing potential of cerebral hemispheres with intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) for whole-ventricular irradiation (WVI) and conventional whole-brain irradiation (WBI) in the management of localized central nervous system germ cell tumors (CNSGCTs). Methods and Materials: Ten cases of patients with localized CNSGCTs and submitted to WVI by use of IMRT with or without a ""boost"" to the primary lesion were selected. For comparison purposes, similar treatment plans were produced by use of 3D-CRT (WVI with or without boost) and WBI (opposed lateral fields with or without boost), and cerebral hemisphere sparing was evaluated at dose levels ranging from 2 Gy to 40 Gy. Results: The median prescription dose for WVI was 30.6 Gy (range, 25.2-37.5 Gy), and that for the boost was 16.5 Gy (range, 0-23.4 Gy). Mean irradiated cerebral hemisphere volumes were lower for WVI with IMRT than for 3D-CRT and were lower for WVI with 3D-CRT than for WBI. Intensity-modulated radiotherapy was associated with the lowest irradiated volumes, with reductions of 7.5%, 12.2%, and 9.0% at dose levels., compared with 3D-CRT. Intensity-modulated radiotherapy provided of 20, 30, and 40 Gy, respectively statistically significant reductions of median irradiated volumes at all dose levels (p = 0.002 or less). However, estimated radiation doses to peripheral areas of the body were 1.9 times higher with IMRT than with 3D-CRT. Conclusions: Although IMRT is associated with increased radiation doses to peripheral areas of the body, its use can spare a significant amount of normal central nervous system tissue compared with 3D-CRT or WBI in the setting of CNSGCT treatment. (C) 2010 Elsevier Inc.

Involvement of the central nervous system in patients with dengue virus infection

The findings of a neurological evaluation in 85 patients with confirmed, acute, dengue virus infection are described. Signs of central nervous system involvement were present in IS patients (21.2%). The most frequent neurological symptom was mental confusion. The frequency of neurological involvement did not differ between patients with primary and secondary dengue infection, and the prevalence of central nervous system involvement in dengue fever and dengue hemorrhagic fever also did not differ significantly. The presence of CNS involvement did not influence the prognosis of dengue infection. Dengue viral CSF RNA was found in 7 of 13 patients submitted to a spinal tap, the CSF viral load being less than 1000 copies/ml. PCR was negative in serum samples obtained from three patients on the same day as the CSF samples, suggesting that the dengue virus actively enters the CNS and that the presence of the virus in the CNS does not result from passive crossing of the blood-brain barrier. (C) 2007 Elsevier B.V. All rights reserved.

Impact of Nervous System Hyperalgesia on Pain, Disability, and Quality of Life in Patients With Knee Osteoarthritis: A Controlled Analysis

Objective. Refractory, disabling pain associated with knee osteoarthritis (OA) is usually treated with total knee replacement. However, pain in these patients might be associated with central nervous sensitization rather than peripheral inflammation and injury. We evaluated the presence of hyperalgesia in patients scheduled for a total knee replacement due to knee osteoarthritis with refractory pain, and we assessed the impact of pressure pain threshold measurements (PPT) on pain, disability, and quality of life of these patients. Methods. Sixty-two female patients were compared with 22 age-matched healthy controls without reported pain for the last year. PPT was measured at the lower extremities subcutaneous dermatomes, over the vastus medialis, adductor longus, rectus femoris, vastus lateralis, tibialis anterior, peroneus longus, iliacus, quadratus lumborum and popliteus muscles and at the supraspinous ligaments from L1-L5, over the L5-S1 and S1-S2 sacral areas and at the pes anserinus bursae and patellar tendon. Results. Patients with knee OA had significantly lower PPT over all evaluated structures versus healthy control subjects (P < 0.001). Lower PPT values were correlated with higher pain intensity, higher disability scores, and with poorer quality of life, except for the role-emotional and general health status. Combined PPT values over the patellar tendon, at the S2 subcutaneous dermatome and at the adductor longus muscle were the best predictors for visual analog scale and Western Ontario and McMaster Universities Osteoarthritis Index pain scores. Conclusion. Patients with pain due to osteoarthritis who were scheduled for total knee replacement showed hyperalgesia of nervous system origin that negatively impacted pain, knee functional capacity, and most aspects of quality of life.

Baroreflex deficit blunts exercise training-induced cardiovascular and autonomic adaptations in hypertensive rats

P>1. Baroreceptors regulate moment-to-moment blood pressure (BP) variations, but their long-term effect on the cardiovascular system remains unclear. Baroreceptor deficit accompanying hypertension contributes to increased BP variability (BPV) and sympathetic activity, whereas exercise training has been associated with an improvement in these baroreflex-mediated changes. The aim of the present study was to evaluate the autonomic, haemodynamic and cardiac morphofunctional effects of long-term sinoaortic baroreceptor denervation (SAD) in trained and sedentary spontaneously hypertensive rats (SHR). 2. Rats were subjected to SAD or sham surgery and were then further divided into sedentary and trained groups. Exercise training was performed on a treadmill (five times per week, 50-70% maximal running speed). All groups were studied after 10 weeks. 3. Sinoaortic baroreceptor denervation in SHR had no effect on basal heart rate (HR) or BP, but did augment BPV, impairing the cardiac function associated with increased cardiac hypertrophy and collagen deposition. Exercise training reduced BP and HR, re-established baroreflex sensitivity and improved both HR variability and BPV. However, SAD in trained SHR blunted all these improvements. Moreover, the systolic and diastolic hypertensive dysfunction, reduced left ventricular chamber diameter and increased cardiac collagen deposition seen in SHR were improved after the training protocol. These benefits were attenuated in trained SAD SHR. 4. In conclusion, the present study has demonstrated that the arterial baroreflex mediates cardiac disturbances associated with hypertension and is crucial for the beneficial cardiovascular morphofunctional and autonomic adaptations induced by chronic exercise in hypertension.

Oral tolerance reduces Th17 cells as well as the overall inflammation in the central nervous system of EAE mice

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory immune response directed against myelin antigens of the central nervous system. In its murine model, EAE, Th17 cells play an important role in disease pathogenesis. These cells can induce blood-brain barrier disruption and CNS immune cells activation, due to the capacity to secrete high levels of IL-17 and IL-22 in an IL-6 + TGF-beta dependent manner. Thus, using the oral tolerance model, by which 200 mu g of MOG 35-55 is given orally to C57BL/6 mice prior to immunization, we showed that the percentage of Th17 cells as well as IL-17 secretion is reduced both in the periphery and also in the CNS of orally tolerated animals. Altogether, our data corroborates with the pathogenic role of IL-17 and IFN-gamma in EAE, as its reduction after oral tolerance, leads to an overall reduction of pro-inflammatory cytokines, such as IL-1 alpha, IL-6, IL-9, IL-12p70 and the chemokines MIP-1 beta, RANTES, Eotaxin and KC in the CNS. It is noteworthy that this was associated to an increase in IL-10 levels. Thus, our data clearly show that disease suppression after oral tolerance induction, correlates with reduction in target organ inflammation, that may be caused by a reduced Th1/Th17 response. Crown Copyright (c) 2010 Published by Elsevier B.V. All rights reserved.

Cerebrospinal fluid levels of chemokines in HIV infected patients with and without opportunistic infection of the central nervous system

Chemokines are chemoattractant cytokines involved in the immune response of a wide variety of diseases. There are few studies assessing their role in opportunistic infections in HIV-infected patients. In this study, we measured CC and CXC chemokines in cerebrospinal fluid (CSF) samples obtained from 40 HIV-infected patients with or without opportunistic infections of the central nervous system (CNS). CSF samples were also analyzed for quantification of total protein, cell count and HIV-1 RNA. HIV+ patients with cryptococcal meningitis had higher levels of CCL2, CCL3, CCL5, CXCL9 and CXCL10 when compared to patients without opportunistic neurological infections. Furthermore, HIV+ patients with associated cryptococcal meningitis had higher levels of CCL3, CXCL9 and CXCL10 when compared to HIV+ patients with associated toxoplasmic encephalitis. CCL3 and CXCL9 levels were positively correlated with CSF HIV-1 RNA levels, CSF protein concentration, and CSF cell count. CXCL10 level was correlated with the CSF viral load and the CSF cell count and CCL5 level was correlated with the CSF cell count. In conclusion, the profile of chemokines in CSF of HIV patients may differ according to the modality of the presented opportunistic infection and according to other biological markers, such as viral load in CSF. These differences are probably related to different patterns of neuroinflammatory responses displayed by patients with different opportunistic neurological infections. (C) 2009 Elsevier B.V. All rights reserved.

Physiological Responses to Brain Stimulation During Limbic Surgery: Further Evidence of Anterior Cingulate Modulation of Autonomic Arousal

Background: In view of conflicting neuroimaging results regarding autonomic-specific activity within the anterior cingulate cortex (ACC), we investigated autonomic responses to direct brain stimulation during sterecitactic limbic surgery. Methods: Skin conductance activity and accelerative heart rate responses to multi-voltage stimulation of the ACC (n = 7) and paralimbic subcauclate (n = 5) regions were recorded during bilateral anterior cingulotomy and bilateral subcauclate tractotomy (in patients that had previously received an adequate lesion in the ACC), respectively. Results: Stimulations in both groups were accompanied by increased autonomic arousal. Skin conductance activity was significantly increased during ACC stimulations compared with paralimbic targets at 2 V (2.34 +/- .68 [score in microSiemens +/- SE] vs. .34 +/- .09, p = .013) and 3 V (3.52 +/- .86 vs. 1.12 +/- .37, p = .036), exhibiting a strong ""voltage-response"" relationship between stimulus magnitude and response amplitude (difference from 1 to 3 V = 1.15 +/- .90 vs. 3.52 +/- .86, p = .041). Heart rate response was less indicative of between-group differences. Conclusions: This is the first study of its kind aiming at seeking novel insights into the mechanisms responsible for central autonomic modulation. It supports a concept that interregional interactions account for the coordination of autonomic arousal.

Sleep-related changes in hemodynamic and autonomic regulation in human hypertension

Objectives The present study investigates the hemodynamic and autonomic regulation during sleep-awake transitions and across different sleep cycles in patients with essential hypertension. Methods Nineteen individuals free of sleep apnea (10 normotensive and nine hypertensive matched for age, sex, and body mass index) underwent a standard polysomnography, with simultaneous electrocardiography and beat-to-beat blood pressure monitoring (Portapres). All measurements were determined while awake (before and after sleep), as well as in the beginning and at end of the sleep cycle (first/last cycle of nonrapid and rapid eye movement stages). Results Systolic blood pressure was higher in hypertensives and exhibited a similar reduction to the normotensives ones in initial nonrapid eye movement sleep. This reduction was because of different mechanisms: a significant fall in cardiac output in normotensives, whereas in hypertensives was also dependent of a decrease in peripheral vascular resistance. Hypertensive patients presented lower heart rate variation and attenuated baroreflex sensitivity during sleep but not immediately before and after sleep. Spectral analysis suggested a higher sympathetic activity in the sleep stages in hypertension. Additionally, a progressive sympathetic predominance (final rapid eye movement> initial rapid eye movement and awake period postsleep> awake period presleep) was observed in both groups. Conclusion Hypertension is associated with depressed baroreflex sensitivity and increased sympathetic activation during sleep. The greater sympathetic predominance at the end of night (preceding the morning surge of sympathetic activity) could be implicated in the occurrence of cardiovascular events. J Hypertens 27: 1655-1663 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Toxoplasma gondii: The severity of toxoplasmic encephalitis in C57BL/6 mice is associated with increased ALCAM and VCAM-1 expression in the central nervous system and higher blood-brain barrier permeability

In order to investigate the differential ALCAM, ICAM-1 and VCAM-1 adhesion molecules mRNA expression and the blood-brain barrier (BBB) permeability in C57BL/6 and BALB/c mice in Toxoplasma gondii infection, animals were infected with ME-49 strain. It was observed higher ALCAM on day 9 and VCAM-1 expression on days 9 and 14 of infection in the central nervous system (CNS) of C57BL/6 compared to BALB/c mice. The expression of ICAM-1 was high and similar in the CNS of both lineages of infected mice. In addition, C57BL/6 presented higher BBB permeability and higher IFN-gamma and iNOS expression in the CNS compared to BALB/c mice. The CNS of C578L/6 mice presented elevated tissue pathology and parasitism. In conclusion, our data suggest that the higher adhesion molecules expression and higher BBB permeability contributed to the major inflammatory cell infiltration into the CNS of C57BL/6 mice that was not efficient to control the parasite. (C) 2010 Elsevier Inc. All rights reserved.