Reduced neural baroreflex sensitivity is related to enhanced endothelial function in patients with end-stage liver disease.

OBJECTIVES: Reduced baroreflex sensitivity (BRS) is a frequent complication in end-stage liver disease, but the underlying mechanism is unknown. We investigated the mechanical and neural components of BRS. Increased nitric oxide (NO) production has been reported in end-stage liver failure. Based on earlier experiments, we hypothesised that enhanced endothelial function might affect baroreflex function. Therefore, we explored the relation between endothelial function and the components of BRS. MATERIALS AND METHODS: We enrolled 24 patients and 23 controls. BRS was determined by the spontaneous sequence method. Mechanical component was characterised by the distensibility coefficient (DC) of common carotid artery. Neural component was estimated as the ratio of integrated BRS and DC. Endothelial function was quantified by flow-mediated dilation (FMD) of the brachial artery. RESULTS: Integrated BRS was reduced in patients [7.00 (5.80-9.25) vs. 11.1 (8.50-14.80) ms/mmHg]. The mechanical component was not different in the two groups, whereas neural component showed significant reduction in patients (3.54 ± 1.20 vs. 4.48 ± 1.43 ms/10-3). FMD was higher in patients (9.81 ± 3.77 vs. 5.59 ± 1.36%). FMD and neural BRS were directly related in controls (r = 0.62), but inversely related in patients (r = -0.49). CONCLUSIONS: Baroreflex impairment in end-stage liver disease might be explained by deterioration of the neural component, while the mechanical component appears to be preserved. Endothelial NO may enhance BRS in health; however, central endothelial overproduction of NO likely contributes to the reduction of neural component of BRS in patients awaiting liver transplantation.

Impaired baroreflex function is related to reduced carotid artery elasticity in patients with tetralogy of Fallot.

Sudden cardiac death (SCD) is a common late complication in patients with tetralogy of Fallot (ToF). Reduced baroreflex sensitivity (BRS) is an independent predictor of SCD and BRS reduction was reported in ToF. Relationship between BRS and carotid artery distensibility (DC) in healthy subjects was reported by us earlier. We also found that DC was reduced in ToF patients. In the present study we tested the hypothesis that reduced BRS is related to increased carotid artery stiffness. We studied 36 ToF patients (21±11 years) and 60 age-matched healthy control subjects. Intravenous phenylephrine-induced (BRSphe) and spontaneous (BRSseq) BRS indices were derived. DC calculation was based on echo wall-tracking and tonometry. BRS indices were reduced in patients compared with controls (BRSphe 16.8±10.2 vs. 27.3±9.2ms/mmHg; BRSseq 9.3±9.2 vs. 18.3±7.8ms/mmHg). DC was also lower in patients (5.1±1.8 vs. 6.3±2.610(-3)/mmHg). BRS correlated with DC across patients and controls (BRSphe r=0.75 vs. r=0.74; BRSseq r=0.44 vs. r=0.38). Multiple regression analysis indicated that BRS indices are determined independently by DC in ToF patients. We showed that reduced DC may contribute to impaired baroreflex function in ToF patients and could in part explain the elevated risk for SCD postoperatively. Therefore it would be an important future investigation to test carotid artery stiffness and analyze its predictive value for cardiac mortality in ToF. Preventive actions to impede carotid artery stiffening should receive more attention in the clinical management of ToF patients.

Genetic impact dominates over environmental effects in development of carotid artery stiffness: a twin study.

Arterial stiffness is an independent predictor of cardiovascular, cerebrovascular and all-cause mortality. Quantifying the genetic influence on the stiff arterial phenotype allows us to better predict the development of arterial stiffness. In this study, we aimed to determine the heritability of carotid artery stiffness in healthy twins. We studied 98 twin pairs of both sexes. We determined carotid artery stiffness locally using echo tracking and applanation tonometry. We estimated the heritability of stiffness parameters using structural equation modeling. The carotid distensibility coefficient showed the highest heritability (64%, 95% confidence interval 45-77%). The incremental elastic modulus, compliance and stiffness index ß also showed substantial heritability (62%, 61% and 58%, respectively). The remaining 36-42% phenotypic variance was attributed to unshared environmental effects. Genetic influence appears to dominate over environmental factors in the development of carotid artery stiffness. Environmental factors may have an important role in favorably influencing the genetic predisposition for accelerated arterial stiffening.

Relationship between heart rate variability and endothelial function in healthy subjects.

In various diseased states reduced cardiac vagal activity is accompanied by impaired endothelial function. Evidence from animal studies indicates interaction between the two systems, but such data from human studies is limited. The aim of this study was to test the hypothesis that cardiac vagal activity and endothelial function are related in healthy individuals. 46 young males were studied. From 10 minute long ECG recordings mean RR-interval and time and frequency domain vagal heart rate variability indices (RMSSD; pNN50 and HF, respectively) were determined. Heart rate variability indices were used to define cardiac vagal activity. Endothelial function was assessed by measuring brachial artery flow mediated dilation. Hyperemic, diastolic shear rate was used to normalize flow mediated dilation. All three vagal heart rate variability indices correlated significantly and positively with flow mediated dilation across subjects, with r values within the range of 0.43-0.52, p<0.01 for all relations. After adjusting for potential confounders, vagal heart rate variability indices remained significantly associated with normalized flow mediated dilation. RR-interval was related to most heart rate variability indices, but was not related to flow mediated dilation. Our data demonstrate that vagal heart rate variability indices are related to flow mediated dilation across healthy male subjects. The results cannot serve as evidence of a causal relationship, but are of interest and render for further investigation into underlying mechanisms.

Carotid artery stiffness is not related to endothelial function in young healthy subjects.

INTRODUCTION: Carotid artery stiffness, an important determinant of arterial baroreflex sensitivity, varies considerably in healthy individuals, the source of which variability is not known. Tonic relaxant influence of the endothelium on vascular smooth muscle, reducing stiffness of the vessel wall, has been established in muscular conduit arteries. It is not known to what extent stiffness of the elastic carotid artery is under endothelial control. SUBJECTS AND METHODS: Seventy-one healthy male volunteers were studied. Endothelial function was assessed by brachial artery flow mediated dilatation (FMD) normalized by diastolic shear rate (SRd). Carotid artery elastic parameters were determined by echo wall-tracking and tonometry. Systemic arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWV). RESULTS: In univariate analysis carotid artery elastic parameters were related to BMI and systolic blood pressure, but were not related to any of endothelial function parameters. As expected, PWV was related inversely to nFMD. No relation was found between vascular stiffness parameters and endothelium-independent dilation (EID). CONCLUSION: Carotid artery elasticity in health is not related to conduit artery FMD, suggesting that endothelial influence on baroreceptor activity is not exerted through changes in barosensory wall elasticity.

Reversible autonomic dysfunction during antiviral treatment in patients with chronic hepatitis C virus infection: Anti-HCV therapy and autonomic function.

BACKGROUND: The first clinical sign of chronic hepatitis C virus (HCV) infection can be one of the various extrahepatic manifestations. During antiviral treatment, symptoms of HCV-associated neuropathies usually improve, but can also worsen and lead to discontinuation of anti-HCV therapy. Recently, we have reported autonomic dysfunction in patients with HCV infection. OBJECTIVES: In the present prospective study, we analyzed the changes of autonomic function during anti-HCV treatment. PATIENTS AND METHODS: Cardiovagal autonomic function was assessed in 22 HCV RNA-positive, treatment-naive patients by determining heart rate variability (HRV) and baroreflex sensitivity (BRS), at the beginning of treatment and 12, 24 and 48 weeks of antiviral therapy. interferon alfa-2 and ribavirin were given according to the guidelines. RESULTS: Both HRV and BRS time and frequency domain indices decreased after 12 weeks of therapy compared to the pre-treatment values; then the mean±SD values increased significantly by week 24 and continued to improve by week 48 of therapy-253.0±156.1 ms before therapy vs 111.6±81.9 at week 12, and 183.4±169.6 at week 24 vs 211.6±149.1 ms at week 48 for low-frequency HRV index; p<0.05 for all comparisons). These changes were independent from the presence of cryoglobulins and from virologic response. CONCLUSIONS: The first rise followed by reversible autonomic dysfunction during antiviral therapy may be caused by the immunomodulatory actions of interferon alfa-2.

Impaired carotid artery elastic function in patients with tetralogy of Fallot.

Complex congenital heart diseases with abnormal formation of the aorticopulmonary septum are also associated with defective large artery elastogenesis. In the current study, we tested the hypothesis that carotid artery elastic function was impaired in patients with tetralogy of Fallot (ToF). The study included 45 Fallot-patients (male:female 27:18; age 21.0 ± 11.8 years) and 45 age- and gender-matched healthy control individuals. Carotid artery diameter, pulsatile distension, and intima-media thickness (IMT) were measured by echotracking device, and carotid blood pressure was determined using applanation tonometry. Carotid artery elasticity was characterized by compliance and distensibility coefficients, stiffness index ß, and incremental elastic modulus. All carotid artery elastic parameters showed significant differences between groups. The compliance coefficient was 36%, and the distensibility coefficient was 33% smaller, whereas stiffness index ß was 46% and incremental elastic modulus was 40% larger in Fallot-patients. Fallot-patients also had larger carotid artery IMT as compared to that of healthy individuals. Carotid artery is markedly stiffer in Fallot-patients suggesting that impaired elastogenesis is a component of the congenital abnormality. Increased large artery stiffness might contribute directly and indirectly (through impairment of baroreflex function) to the higher mortality found in ToF patients.

Evolution and predictors of morphological and functional arterial changes in the course of type 1 diabetes mellitus.

BACKGROUND: Diabetes mellitus results in accelerated atherosclerosis. We evaluated preclinical, morphological and functional vascular changes in type 1 diabetes mellitus. METHODS: Diameter, intima-media thickness, intima-media cross-section area, and elasticity features (compliance, distensibility coefficient, circumferential strain, stiffness index, incremental elastic modulus) of the common carotid arteries and carotid-femoral pulse wave velocity were studied in 42 patients with type 1 diabetes mellitus without macroangiopathy, and 41 control subjects matched for sex, age and body mass index using an ultrasonographic vessel wall-movement tracking system and applanation tonometry. RESULTS: Significantly larger intima-media thickness (523 ± 55 versus 567 ± 89 µm, p < 0.01), intima-media cross-section area (11.60 ± 1.81 versus 13.08 ± 3.02 mm(2) , p < 0.01), SI (5.58 ± 1.24 versus 7.08 ± 2.69, p < 0.01) and pulse wave velocity (6.00 ± 0.82 versus 6.61 ± 1.56 m/s, p < 0.05) were found in type 1 diabetes mellitus patients compared to controls. When type 1 diabetes mellitus patients with short and long disease duration (≤ or > 10 years) were compared, diameter (6450 ± 433 versus 6847 ± 750 µm, p < 0.05), intima-media cross-section area (11.97 ± 1.98 versus 14.01 ± 3.43 mm, p < 0.05) and pulse wave velocity (5.90 ± 0.92 versus 7.20 ± 1.74 m/s, p < 0.01) differed significantly. When multivariate analyses were restricted to type 1 diabetes mellitus patients, age was an independent predictor of stiffness index and pulse wave velocity, the duration of diabetes mellitus of intima-media cross-section area and pulse wave velocity, systolic blood pressure of diameter and pulse wave velocity, and low-density lipoprotein-cholesterol of intima-media thickness, intima-media cross-section area and stiffness index. CONCLUSIONS: There are differences in the time course of evolution and in predictors of morphological and functional changes in arteries in type 1 diabetes mellitus.

Biomechanics of resistance artery wall remodeling in angiotensin-II hypertension and subsequent recovery.

BACKGROUND/AIMS: To identify the relationship between systemic and local hemodynamics, as well as segmental biomechanical properties in a musculocutaneous resistance artery during angiotensin-II hypertension and its recovery. METHODS: Rats were infused with angiotensin-II using implanted osmotic minipumps (ALZET 2ML4, 150 ng/kg/min) for 4 weeks. Measurements were made either immediately following infusion or after an additional 4-week recovery period. Parallel controls were created. Segmental geometry and blood flow were determined in vivo on microsurgically exposed segments of the saphenous arterial branch (350 mum). Pressure-radius plots of excised cylindrical segments were recorded by pressure arteriography. RESULTS: Eutrophic hypertensive wall remodeling developed, with reduced passive radius, increased wall thickness, elevated low-stress elastic modulus, reduced norepinephrine contraction, and reduced endothelium-mediated dilation. Relaxed wall geometry fully healed in 4 weeks of recovery, but an increased contractility and a reduced in vivo lumen persisted. Regional hemodynamic resistance correlated positively with systemic arterial pressure and wall thickness in vivo, and negatively with in vivo lumen size throughout these studies. CONCLUSION: A partial recovery of the biomechanical parameters was found. Healing of eutrophic hypertensive remodeling of the resistance artery wall is a complex biomechanical process, not a simple reversal of the original pathological sequel.

Chronic hepatitis C virus infection associated with autonomic dysfunction.

BACKGROUND: Impaired autonomic function has been described in patients with chronic liver diseases from different aetiologies, and has proven to be a poor prognostic indicator. To date, it is not known how chronic hepatitis C virus (HCV) infection affects the autonomic nervous system. AIMS: In the present study, we compared cardiovagal autonomic function in patients with chronic HCV infection and healthy controls and examined the relation between autonomic function and serum levels of aminotransferases, HCV RNA, cryoglobulins, albumin and glucose. METHODS: Autonomic function was assessed in 45 treatment-naïve patients with chronic HCV infection and in 40 healthy controls by determining spontaneous baroreflex sensitivity (BRS) and heart rate variability (HRV) indices. The R-R interval was determined by electrocardiogram recording; continuous radial artery pressure was monitored simultaneously by applanation tonometry. Laboratory analyses and quantitative polymerase chain reaction for serum HCV RNA level were performed by standard procedures. RESULTS: BRS and HRV time and frequency domain indices were lower in patients with HCV infection compared with healthy controls [7.1+/-3.4 vs. 11.5+/-6.5 ms/mmHg for BRS, 168.5+/-160.9 vs. 370.7+/-349.4 ms(2) for low-frequency HRV (mean+/-SD); P<0.01]. Multivariate analysis showed that autonomic dysfunction in HCV-infected patients correlated with elevated alanine aminotransferase levels, but was not associated with serum HCV RNA levels and cryoglobulins. CONCLUSION: Our results suggest that impaired autonomic function is caused by chronic HCV infection. Further studies are needed, however, to identify the underlying mechanisms.

Use of generalized transfer function-derived central blood pressure for the calculation of baroreflex gain.

BACKGROUND: Peripheral blood pressure measurement underestimates pressure changes during baroreflex testing, resulting in an overestimation of baroreflex gain. This error might be reduced by measuring central blood pressure; the invasive measurement, however, may represent ethical and practical problems. The solution may be the derivation of central blood pressure from the peripheral pulse using a generalized transfer function. METHODS: In the current study, we tested the agreement between catheter-measured and generalized transfer function derived central blood pressure measurements and corresponding baroreflex gains. ECG and blood pressure waveforms were monitored continuously during a phenylephrine-induced pressure rise in 22 subjects undergoing cardiac catheterization. Pressure was measured with a catheter positioned in the aorta and with applanation tonometry in the radial artery. Radial pressure waveforms were subject to a generalized transfer function built in the SphygmoCor device to derive central pressure waveforms. Radial tonometric signal was calibrated with catheter-measured (invasive) and sphygmomanometric (noninvasive) pressures. Baroreflex gains were calculated from the linear regressions between heart period and systolic pressure changes. RESULTS: When radial tonometric signal was calibrated invasively, there was no group difference between baroreflex gains calculated from SphygmoCor-derived and catheter-measured pressures (8.2 +/- 1.2 vs. 7.2 +/- 1.2 ms/mmHg, P = NS). When radial tonometric signal was calibrated noninvasively, however, baroreflex gains calculated from SphygmoCor-derived pressures overestimated those calculated from catheter-measured pressures. CONCLUSION: Using a generalized transfer function is an accurate method to derive central pressure changes for baroreflex gain calculation. The technique, however, requires invasive pressure measurements for calibration, leaving the problem of a fully noninvasive central pressure measurement unresolved.

Decreased cardiovagal regulation in exfoliation syndrome.

PURPOSE: To investigate the parasympathetic cardiovascular regulation, baroreflex sensitivity (BRS), and pulse wave velocity (PWV) in exfoliation syndrome (XFS). METHODS: Heart rate variability indices [standard deviation of all RR intervals (SDNN); the mean of absolute successive differences (RMSSD); the percentage of intervals differing by >50 ms from the preceding interval (pNN50); low frequency power, and high frequency power], as well as BRS and PWV, were determined on 27 consecutive white XFS patients and 20 white control subjects under standard circumstances, with controlled breath rate of 0.25 Hz. The paired t test, the Mann-Whitney U test, and the Fisher exact test were used for comparisons. RESULTS: There was no significant difference between the XFS and control groups in sex distribution, age, heart rate, blood pressure, body mass index, systemic diseases, or medication. But in XFS patients, SDNN (mean+/-SD, 24+/-7.3 vs. 49+/-16.5 ms), RMSSD (17+/-7.3 vs. 45+/-29.1 ms), pNN50 (1.6%+/-2.5% vs. 17.7%+/-25.9%), high frequency (112+/-109 vs. 479+/-554 ms), and BRS (4.64+/-2.12 vs. 9.49+/-4.76 ms/mm Hg for BRS+ and 5.28+/-2.16 vs. 10.29+/-4.62 ms/mm Hg for BRS-) were all significantly lower than in the control group (P<0.01 for each parameter). Low frequency was also reduced in XFS (72+/-55 vs. 253+/-241 ms) (P=0.027). In XFS, PWV was significantly increased compared with the control group (11.6+/-4.1 vs. 9.3+/-2.2 m/s) (P=0.023). DISCUSSION: Our results suggest a clinically and statistically significant impairment of cardiovagal regulation and impairment of conduit artery function in XFS patients.

[The pH of the exhaled breath condensate: new method for investigation of inflammatory airway diseases]. / A kilégzett levego kondenzátumának pH-ja: új lehetoség a gyulladásos légúti betegségek vizsgálatában.

Collecting exhaled breath condensate (EBC) has become a frequently used method in respiratory researches to date. Through this method we can sample airway surface liquid non-invasively by streaming the exhaled breath through a cooled chamber and after we examine the fluid deposited on the wall of the condenser. The sample contains several mediators, biomarkers. The pH of the condensate is one of the most important markers measured in the EBC. Measuring the pH is easy, cheap and it is in the optimal range, there is no problem with the detection limit. The uncertainty of the pH assays is derived from the instability of the EBC pH which results from the altering carbon-dioxide concentration. Many articles have been published on EBC pH in different airway diseases. Acidification of the condensates has been described in bronchial asthma (especially in acute exacerbations), chronic obstructive lung disease (COPD). Due to the steroid treatment the pH has increased in both cases. In patients with bronchiectasis, cystic fibrosis and in chronic cough (bronchial asthma, gastro-esophageal reflux, postnasal drip, and unknown origin) the pH of EBC was also lower. Acidification of the airways in different diseases can play a role in the pathomechanism, and its indicator, the EBC pH might help managing patients with airway diseases.

Adaptation of baroreflex function to increased carotid artery stiffening in patients with transposition of great arteries.

We have shown previously that TGA (transposition of great arteries) is associated with increased carotid artery stiffness. It has been established that stiffening of the barosensory vessel wall results in reduced baroreceptor activation and impaired BRS (baroreflex sensitivity). In the present study we tested the hypothesis that the increased carotid artery stiffness in TGA patients was associated with reduced cardiovagal BRS. We studied 32 TGA patients aged 9-19 years, 12+/-3 years after surgical repair and 32 age-matched healthy control subjects. Carotid artery diastolic diameter and pulsatile distension was determined by echo wall tracking; carotid blood pressure was measured by tonometry. BRS was measured using spontaneous techniques [BRS(seq) and LF(gain) (low-frequency transfer function gain)] and by the phenylephrine method (BRS(phe)). Carotid artery distensibility was markedly reduced in patients as compared with controls (5.6+/-1.9 x 10(-3) compared with 8.7+/-2.7 x 10(-3)/mmHg P<0.05, as determined using an unpaired Student's t test), but BRS was not different in patients and controls (20.3+/-14.7 compared with 21.7+/-12.7 for BRS(seq); 13.1+/-9.2 compared with 10.6+/-4.5 for LF(gain); and 19.1+/-8.6 compared with 24.8+/-7.2 for BRS(phe) respectively). Carotid artery elastic function was markedly impaired in patients with TGA, but the increased stiffness of the barosensory vessel wall was not associated with reduced BRS. It appears that attenuation of baroreceptor stimulus due to arterial stiffening may be compensated by other, possibly neural, mechanisms when it exists as a congenital abnormality.

Human heart mitochondria do not produce physiologically relevant quantities of nitric oxide.

Previous studies raised the possibility that nitric oxide synthase is present in heart mitochondria (mtNOS) and the existence of such an enzyme became generally accepted. However, original experimental evidence is rather scarce and positive identification of the enzyme is lacking. We aimed to detect an NOS protein in human and mouse heart mitochondria and to measure the level of NO released from the organelles. Western blotting with 7 different anti-NOS antibodies failed to detect a NOS-like protein in mitochondria. Immunoprecipitation or substrate-affinity purification of the samples concentrated NOS in control preparations but not in mitochondria. Release of NO from live respiring human mitochondria was below 2 ppb after 45 min of incubation. In a bioassay system, mitochondrial suspension failed to cause vasodilation of human mammary artery segments. These results indicate that mitochondria do not produce physiologically relevant quantities of NO in the heart and are unlikely to have any physiological importance as NO donors, nor do they contain a recognizable mtNOS enzyme.

Transposition of great arteries is associated with increased carotid artery stiffness.

Transposition of great arteries is the consequence of abnormal aorticopulmonary septation. Animal embryonic data indicate that septation and elastogenesis are related events, but human and clinical data are not available. We tested the hypothesis that large artery elastic function was impaired in patients with transposition of great arteries. We studied 34 patients aged 9 to 19 years, 12+/-3 years after atrial switch operation; 14 patients aged 7 to 9 years, 8+/-1 years after arterial switch operation; and 108 healthy control subjects matched for age. Carotid artery diastolic diameter and pulsatile distension were determined by echo wall-tracking; carotid blood pressure was measured by tonometry. Systolic pressure was higher and diastolic pressure was lower in patients than in controls. Patients with atrial and arterial switch repair were compared with their respective controls by 2-factor ANOVA. For patients with atrial switch repair versus control, stiffness index beta was 4.9+/-1.5 versus 3.1+/-1.0 (P<0.001); for patients witch arterial switch versus control, stiffness index beta was 3.8+/-1.1 versus 2.1+/-0.6 (P<0.001). Similar differences were observed for carotid compliance, distensibility, and incremental elastic modulus as well. The interaction term was not significant for any of the elastic variables, indicating that carotid stiffening was a characteristic of the condition and not the consequence of different hemodynamics. Carotid artery is markedly stiffer in patients, suggesting that impaired elastogenesis may constitute part of the congenital abnormality. Since carotid artery stiffness has been established as an independent cardiovascular risk factor, this condition may have consequences in the clinical management of these patients.

Mitochondria produce reactive nitrogen species via an arginine-independent pathway.

We measured the contribution of mitochondrial nitric oxide synthase (mtNOS) and respiratory chain enzymes to reactive nitrogen species (RNS) production. Diaminofluorescein (DAF) was applied for the assessment of RNS production in isolated mouse brain, heart and liver mitochondria and also in a cultured neuroblastoma cell line by confocal microscopy and flow cytometry. Mitochondria produced RNS, which was inhibited by catalysts of peroxynitrite decomposition but not by nitric oxide (NO) synthase inhibitors. Disrupting the organelles or withdrawing respiratory substrates markedly reduced RNS production. Inhibition of complex I abolished the DAF signal, which was restored by complex II substrates. Inhibition of the respiratory complexes downstream from the ubiquinone/ubiquinol cycle or dissipating the proton gradient had no effect on DAF fluorescence. We conclude that mitochondria from brain, heart and liver are capable of significant RNS production via the respiratory chain rather than through an arginine-dependent mtNOS.

Mitochondrial NO and reactive nitrogen species production: does mtNOS exist?

It is more than 10 years now that mitochondria are suspected to be sources of nitric oxide (NO). This hypothesis is intriguing since NO has multiple targets within the organelle and it is even suggested that mitochondria are the primary targets of NO in the cell. Most remarkably, nanomolar concentrations of NO can inhibit mitochondrial respiration, so even a small amount of NO in the mitochondrial matrix may regulate ATP synthesis. Therefore, the idea that mitochondria themselves are capable of NO production is an important concept in several physiological and pathological mechanisms. However, this field of research generates surprisingly few original papers and the published studies contain conflicting results. The reliability of the results is frequently questioned since they are seldom reproduced by independent investigators. Until 2003, all papers published in this field showed affirmative results but since then several studies directly challenged the existence of a mitochondrial nitric oxide synthase. The present review aims to summarize the most recent developments in mitochondrial NO production, highlights a few unsolved questions, and proposes new directions for future work in this research area.

Graft derived cells with double nuclei in the penumbral region of experimental brain trauma.

Recent in vitro studies showed that stem cells might fuse with mature cells or each other; however, there is no in vivo evidence for this phenomenon in the cerebral cortex. Our goal was to find evidence for cell fusion in a model of traumatic brain injury followed by grafting of embryonic cortical cells. Cold lesion protocol was applied to induce lesion of the motor cortex in adult male rats. Six days later we grafted a suspension of freshly isolated rat brain cortical cells of early embryonic stage (E14) into the penumbra area of the lesion. The grafted cell nuclei were labelled with bromodeoxyuridine (BrDU). Six days after transplantation 4,328 BrDU positive cells were observed in nine animals. 89.5% of these cells had cytoplasmic staining probably representing dead or phagocyted grafted cells. Ten percent of surviving BrDU positive cells had only one BrDU positive nucleus and negative cytoplasm, while 0.5% had two distinct nuclei, one was unlabelled and one was BrDU positive. These cells were similar in appearance and size to the astrocytes in the vicinity and expressed the astocyte specific glial fibrillaly acidic protein. Thus, these cells showed a possible sign of cell fusion in the penumbral region of the injured brain.

[Investigation of cerebral autoregulation in Parkinson's disease--a transcranial Doppler study]. / Az agyi autoreguláció vizsgálata Parkinson-betegségben.

BACKGROUND AND PURPOSE: The frequent orthostatic intolerance in Parkinson's disease could be the consequence of cardiovascular autonomic failure and/or a damaged cerebral autoregulation (AR). To clarify this question the regulation of cerebral circulation was investigated by polygraphic method. METHODS: On a tilt table simultaneous and continuous registrations were made of MCA velocity (V(MCA)) by transcranial Doppler, arterial blood pressure by non-invasive method, and end-tidal CO2, in supine and in tilted positions of 10 degrees, 30 degrees, 70 degrees grades. The cerebral autoregulation was characterized by the slope of the curve of the arterial blood pressure at the level of the Willis-circle (BP(W) as MCA perfusion pressure) plotted against the MCA velocity, achieved by linear regression (y = ax + b function, a=AR, or index of autoregulation). PATIENTS: The data of 17 parkinsonian patients (PP) and eight age-matched controls (C) were analyzed. RESULTS: The decrease of blood pressure in parkinsonian patients was significantly lower than in the controls when supine position was restored from 70 degrees (deltaABP 70 degrees - 0 degree pp = -3.1 +/- 7.5 Hgmm; deltaABP 70 degrees - 0(C) degrees = -11.1 +/- 7.3 Hgmm; p < 0.05), which suggests a damage to the sympathetic cardiovascular system. A disturbance of the cerebral autoregulation in patients was suggested by a 'progressively decreasing MCA average velocity (V(MCA)) during graded tilt, which was significant at 70 degrees (deltaV(ACM) = 9.8 +/- 8.82% cms(-1); p(C-PP) P 0.5), and by a higher slope of pressure-velocity curve (AR(C) = 0.143 +/- .125% cms(-1)/Hgmm; AR(PP) = 0.38 +/- 0.25% cms(-1)/Hgmm; p(C-PP) < 0.05). CONCLUSIONS: The results show that the cerebral blood flow of patients is more dependent on perfusion pressure compared to healthy controls. The disturbance of the sympathetic cardiovascular system and of cerebral autoregulation could be the consequence of a damage to the postganglionic structures in Parkinson's disease. These results could explain the frequent orthostatic intolerance of patients even with normal blood pressure.