Oral yohimbine in human autonomic failure

Yohimbine is an alpha 2-adrenoreceptor antagonist that acts to enhance sympathetic nervous system discharge and potentiate sympathetically mediated cardiovascular reflex responses. We therefore assessed the ability of yohimbine to increase sympathoadrenal discharge and raise blood pressure (BP) in patients with autonomic failure characterized by profound orthostatic hypotension. Yohimbine 5 mg orally in eight seated patients significantly elevated mean systolic BP by 33 mm Hg from 136 +/- 15 (mean +/- SD) to a maximum of 169 +/- 23 mm Hg (p less than 0.01), mean diastolic BP by 16 mm Hg from 77 +/- 9 to a maximum of 93 +/- 15 mm Hg (p less than 0.01), and mean heart rate (HR) by 10 beats per minute (BPM) from 68 +/- 12 to a maximum of 78 +/- 17 BPM (p less than 0.01). Plasma norepinephrine (NE) increased from 104 +/- 71 to a maximum of 196 +/- 182 pg/ml (p less than 0.05), but plasma epinephrine (E) did not increase significantly (31 +/- 18 versus a maximum of 39 +/- 21 pg/ml). In five patients given yohimbine 2.5 mg orally, BP, HR, NE, and E tended to increase, but the changes were not significant. Plasma yohimbine levels correlated significantly with the changes in mean arterial pressure (r = 0.61, p less than 0.01). Yohimbine raises BP and HR in patients with autonomic failure. These effects are dose- and concentration-dependent and mediated through increased sympathetic discharge. Yohimbine may be useful in the treatment of orthostatic hypotension associated with autonomic failure. It is unique among current modes of therapy for this disorder in that it enhances discharge of the patient's own sympathetic system.     

Effect of parathormone on heart rate variability in hemodialysis patients

INTRODUCTION: Parathormone (PTH) is a very potent uraemic toxin, which affects heart structure and function. PTH also plays the role in uraemic autonomic neuropathy (AN). The aim of the study was to investigate the relationship between high PTH level and AN assessed with frequency domain measures of heart rate variability (HRV). MATERIALS AND METHODS: A 24-h ECG was performed in 40 HD (F=19, M=21) patients aged 49+/-11 years, duration of HD therapy 37+/-30 months. Frequency domain measures of HRV were obtained according to European Society of Cardiology recommendations. Total spectral power (TP), high frequency band (HF) and low frequency band (LF) were computed as indexes of: total autonomic nervous system (ANS) activity, parasympathetic and sympathetic activities, respectively. LF/HF ratio was calculated. TP, HF, LF and LF/HF were expressed as natural logarithm. Patients were divided into two groups due to PTH level: PTH+ (PTH> or =275 pg/ml) and PTH- (PTH<275 pg/ml). RESULTS: The values of lnTP and lnLF were lower in patients PTH+ than in patients PTH- (6,58+/-0,76 vs. 6,99+/-0,44 ms2, p<0,05, and 4,91+/-0,99 vs. 5,33+/-0,65 ms2, respectively, p=0,06). We also found negative correlation between lnPTH and lnTP (r=-0,47; p<0,005), lnPTH and lnLF (r=-0,35; p<0,05), lnPTH and lnHF (r=-0,34; p<0,05). On multiple regression analysis, lnTP, lnLF and lnHF were independently related to lnPTH. CONCLUSIONS: Parathormone exerts effect on activity of both parts of autonomic nervous system: sympathetic and parasympathetic. High PTH level deteriorates total autonomic activity.     

Progressive dysregulation of autonomic and HPA axis functions in HIV-1 clade C infection in South India

Human immunodeficiency virus type 1 (HIV-1) infection causes a wide spectrum of abnormalities in neurological, neuropsychological, and neuroendocrinological functions. Several studies report disturbance in autonomic nervous system (ANS) and hypothalamic pituitary-adrenal (HPA) axis function in HIV-1B infected individuals. However, no such investigations on the effect of HIV-1 clade C infection, particularly during the initial phase of the disease progression, have been reported. The present investigations were carried out longitudinally over a 2-year period at 12 monthly intervals in clinically asymptomatic HIV-1 clade C seropositive patients (n=120) and seronegative control subjects (n=29). We determined both the basal levels and the dynamic changes in plasma levels of norepinephrine (NE), epinephrine (E), adrenocorticotrophic hormone (ACTH) and cortisol (CORT). Studies were also extended longitudinally (at three separate yearly visits of each participant), to evaluate the response of autonomic and HPA axis to mirror star tracing challenge test (MSTCT) and the values were determined as area under the curve (AUC, corrected for baseline levels of NE, E, ACTH, and CORT). The findings show that the values of basal plasma NE levels, as well as NE response to MSTCT (AUC) at the first visit of HIV-1 seropositive individuals did not differ from those found in the control subjects (NE, pg/ml, HIV-1C=313.5+/-12.7 vs. controls=353.0+/-21.3; p=NS; AUC, HIV-1C=225+/-14.75 vs. controls=232.7+/-19.34; p=NS, respectively). At the subsequent two visits of HIV-1 positive patients however, NE response to MSTCT challenge was progressively attenuated (AUC=235+/-19.5 and 162.7+/-13.6; p<0.01 and 0.05, respectively) compared to that found at the first visit. On the other hand, plasma levels of E as well as E response to MSTCT at the first visit were significantly lower in HIV-1C seropositive individuals compared to those in the control subjects (pg/ml, HIV-1C=77.30+/-5.7 vs. controls=119.1+10.5; p<0.05; AUC, HIV-1C =83.29+/-7.5 vs. controls=172.3+/-18.9; p<0.001), but no further change was observed in AUC of E in response to MSTCT at the two subsequent yearly visits. The basal plasma levels of ACTH in HIV-1C seropositives were not different than in the control subjects (pg/ml: HIV-1C=20.0+/-0.9 vs. controls=23.1+/-1.6; p=NS), but ACTH response to MSTCT in HIV-1C seropositive patients at the first visit was lower than in the controls (AUC, HIV-1C=23.57+/-1.5 vs. controls=30.94+/-3.5; p<0.05), and fluctuated between high and low at the second and third visits (AUC, 28.89+/-2.3 and 21.69+/-2.36, respectively). However, the baseline plasma levels of cortisol as well as the response of cortisol to MSTCT (AUC) in HIV-1C seropositive individuals were higher than in the control subjects at the first visit (mug/dl, HIV-1C=9.83+/-0.39 vs. controls=6.3+/-0.56; p<0.05; AUC, HIV-1C=12.31+/-0.7 vs. control=9.18+/-0.9; p<0.05), and remained high at the two subsequent yearly follow up visits of HIV-1C (AUC, 11.8+/-0.86 and 11.98+/-0.77, respectively). These findings demonstrate attenuated autonomic functions, a disconnection between response of ACTH and cortisol to the MSTCT challenge, and an inverse relationship between plasma levels of catecholamine(s) and cortisol. Since plasma catecholamines and cortisol are the peripheral mediators of the autonomic and HPA axis function, the findings of this study reflect the overall adverse effect of HIV-1C infection on autonomic as well as HPA axis functions. The findings, apart from being the first to demonstrate the progressive dysregulation of autonomic nervous system and HPA axis function among HIV-1C infected seropositive individuals much ahead of the onset of acquired immunodeficiency syndrome (AIDS), also suggest that MSTCT, involving visuoconstructive cognitive abilities, is an effective stressor for unraveling the underlying dysfunctions in the neuroendocrine functions in health and disease.     

Reduced plasma norepinephrine response to standing in autonomic dysfunction.

In five patients having primary autonomic dysfunction with clinical manifestations including postural hypotension, the mean plasma norepinephrine concentrations were significantly lower than those of normal subjects after two and five minutes in the standing position. The mean (+/-SE) increment in the plasma norepinephrine concentration after two minutes standing were 123 +/- 19 pg/ml in the normal subjects and 13 +/- 4 pg/ml (P less than .001) in the patients with primary autonomic dysfunction. After five minutes standing, the mean increment in plasma norepinephrine concentration was 244 +/- 36 pg/ml in the normal subjects and 99 +/- 51 pg/ml (P less than .05) in the patients. There were no statistically significant differences in plasma epinephrine between the two groups.     

Increased plasma noradrenaline during severe sodium restriction does not stimulate platelet release in essential hypertension

Seventeen 50-year old hypertensive men, previously untreated with blood pressure 157 +/- 4/110 +/- 2 mmHg (means +/- SE) were given a low sodium diet for 2 weeks. During the second week, the diet was supplemented with potassium. The urinary Na+/K+ excretion ratio changed from 2:1 to 1:4 and 1:11, respectively. Sympathetic noradrenergic tone increased considerably during the first week. Thus, venous plasma noradrenaline increased from 254 +/- 22 to 347 +/- 28 pg/ml (p less than 0.001) and arterial concentration from 253 +/- 36 to 317 +/- 42 pg/ml (n = 10, p less than 0.001). No significant change was observed in sympathetic adrenal tone as reflected by normal plasma adrenaline in venous (42 +/- 5 vs 43 +/- 6 pg/ml, ns) or arterial blood (71 +/- 10 vs 82 +/- 15 pg/ml, n = 10, ns) or in venous plasma concentration of the blood platelet release product beta-thromboglobulin (BTG) (50 +/- 8 vs 43 +/- 5 ng/ml, ns). During the second week sympathetic noradrenergic tone remained highly significantly elevated compared to baseline but still no change in plasma adrenaline or plasma BTG was found. Thus, whereas sodium depletion did increase plasma noradrenaline concentration markedly in these hypertensive men, no change in adrenaline concentration was observed, and blood platelet release reaction was unchanged. Plasma noradrenaline within the physiological concentration range does not seem to serve as a regulator of in vivo platelet function.     

Microinjections of norepinephrine within the superficial laminae of trigeminal subnucleus caudalis evoke increases in plasma adrenocorticotropin in the rat

To determine if local release of norepinephrine within the medullary dorsal horn influences autonomic responses often associated with nociception, microinjections of norepinephrine or of specific adrenergic receptor agonists were directed at the trigeminal subnucleus caudalis (Vc) in pentobarbital-anesthetized rats. Norepinephrine (20 nmol, 100 nl) evoked a significant increase (+ 233.8 +/- 89.5 pg/ml, P less than 0.01) in plasma concentrations of adrenocorticotropin (ACTH) after injections within the superficial laminae (I-II) of Vc, whereas mean arterial pressure or heart rate were not affected. Methoxamine (20 nmol), an alpha 1-adrenoceptor agonist, injections into laminae I-II also increased plasma ACTH (+ 90.6 +/- 32 pg/ml, P less than 0.025) without affecting arterial pressure or heart rate. Norepinephrine injections into the deeper laminae (III-V) of Vc caused a variable increase in plasma ACTH (+ 203.5 +/- 146.5 pg/ml, P less than 0.01) that was not mimicked by injections of methoxamine. Microinjections of alpha 2-(clonidine) or beta-(isoproterenol) adrenergic receptor agonists into Vc had no effect on plasma ACTH regardless of the laminar site of injection. The results suggest that norepinephrine acts within Vc to alter selected autonomic responses often associated with nociception. The involvement of an alpha 1-adrenergic receptor subtype within the superficial laminae of the medullary dorsal horn suggests a neural mechanism for norepinephrine-evoked increase in plasma ACTH that is distinct from the well known alpha 2-adrenergic receptor-mediated antinociceptive effects of norepinephrine.     

Orthostatic hypotension from sympathetic denervation in Parkinson's disease

BACKGROUND: Patients with PD often have signs or symptoms of autonomic failure, including orthostatic hypotension. Cardiac sympathetic denervation occurs frequently in PD, but this has been thought to occur independently of autonomic failure. METHODS: Forty-one patients with PD (18 with and 23 without orthostatic hypotension) and 16 age-matched healthy volunteers underwent PET scanning to visualize sympathetic innervation after injection of 6-[(18)F]fluorodopamine. Beat-to-beat blood pressure responses to the Valsalva maneuver were used to identify sympathetic neurocirculatory failure and plasma norepinephrine to indicate overall sympathetic innervation. RESULTS: All patients with PD and orthostatic hypotension had abnormal blood pressure responses to the Valsalva maneuver and septal and lateral ventricular myocardial concentrations of 6-[(18)F]fluorodopamine-derived radioactivity >2 SD below the normal mean. In contrast, only 6 of the 23 patients without orthostatic hypotension had abnormal Valsalva responses (p < 0.0001 compared with patients with orthostatic hypotension), and only 11 had diffusely decreased 6-[(18)F]fluorodopamine-derived radioactivity in the left ventricular myocardium (p = 0.0004). Of the 12 remaining patients without orthostatic hypotension, 7 had locally decreased myocardial radioactivity. Supine plasma norepinephrine was lower in patients with than in those without orthostatic hypotension (1.40 +/- 0.15 vs 2.32 +/- 0.26 nmol/L, p = 0.005). 6-[(18)F]fluorodopamine-derived radioactivity was less not only in the myocardium but also in the thyroid and renal cortex of patients with PD than in healthy control subjects. CONCLUSIONS: In PD, orthostatic hypotension reflects sympathetic neurocirculatory failure from generalized sympathetic denervation.     

Simultaneous monitoring of endothelin-1 and vasopressin plasma levels in migraine

Vasopressin levels in plasma rise during migraine attacks. Vasopressin also induces endothelin-1 synthesis in endothelial cells, suggesting a role as a mediator of elevated plasma endothelin-1 in migraine. To explore a possible relationship between endothelin-1 and vasopressin in migraine, plasma concentrations of both peptides were monitored simultaneously throughout an attack and during two migraine-free intervals (control) in 20 patients. Endothelin-1 was elevated 6 h after the onset of an attack (3.3 +/- 0.3 pg/ml vs 2.7 +/- 0.2 pg/ml during migraine-free intervals; p = 0.12) whereas vasopressin was increased over control levels (2.8 +/- 0.3 pg/ml) by 3 h (3.6 +/- 0.4 pg/ml; p < 0.05) and remained elevated at 6 h (3.9 +/- 0.5 pg/ml; p < 0.01). These data suggest that vasopressin may act as a peripheral mediator of increased plasma endothelin-1 in migraine.     

The release of tumor necrosis factor-alpha is associated with ischemic tolerance in human stroke

Tumor necrosis factor (TNF)-alpha overexpression has been related to experimental ischemic tolerance when transient ischemia precedes cerebral infarction. We investigated TNF-alpha and interleukin (IL)-6 plasma concentrations in 283 patients with an acute stroke within 24 hours after symptom onset. An ipsilateral transient ischemic attack (TIA) within 72 hours before stroke was recorded in 38 patients. The infarct volume measured on computed tomography on days 4 to 7 and the frequency of poor outcome (Barthel Index score < 85) at 3 months were significantly lower in patients with prior TIA. Plasma concentrations of TNF-alpha were higher (42.5 +/- 9.9 vs 13.1 +/- 6.4pg/ml, p < 0.0001) and IL-6 levels were lower (10.1 +/- 6.2 vs 28.3 +/- 17.3pg/ml, p < 0.0001) in patients with prior TIA. A new variable termed TNF-alpha/IL-6 index was considered positive when TNF-alpha was greater than 30pg/ml and IL-6 was less than 30pg/ml. Positive TNF-alpha/IL-6 index was found in 92% of patients with prior TIA and in 1% of those without. TNF-alpha/IL-6 index (p = 0.0003) and TIA (p = 0.0001) were associated with good outcome in logistic regression analysis after adjusting for potential confounding factors. Ischemic tolerance in acute stroke is associated with increased plasma levels of TNF-alpha in the presence of reduced concentrations of IL-6.     

Nocturnal hypertension in mice consuming a high fructose diet

OBJECTIVE: To investigate the effect of fructose consumption on the light/dark pattern of blood pressure, heart rate and autonomic neural function in mice. BACKGROUND: Insulin resistant diabetes is associated with hypertension and autonomic dysfunction. There is evidence that the increasing incidence of diabetes may be related to dietary changes, including consumption of high levels of fructose. DESIGN/METHODS: C57/BL mice, instrumented with radiotelemetric arterial catheters, were fed a control or high fructose diet (60%). Cardiovascular parameters measured were light/dark pattern of mean arterial pressure (MAP), heart rate (HR) and variability (time and frequency domain). We also measured plasma insulin, glucose, lipids and angiotensin II (Ang II) as well as glucose tolerance. In situ hybridization was used to measure brainstem expression of tyrosine hydroxylase (TH) and Ang AT1a mRNA. RESULTS: Fructose diet (8 weeks) produced an increase in MAP, variance and low frequency domain (14+/-3 vs. 33+/-4 mm Hg(2), variance and 10+/-2 vs. 26+/-4 mm Hg(2), LF, control vs. fructose, P<0.01). The changes occurred only at night, a period of activity for mice. Glucose tolerance was attenuated in the fructose group. Fructose also increased plasma cholesterol (80+/-1 vs. 126+/-2 mg/dl, control vs. fructose, P<0.05) and plasma Ang II (18+/-5 vs.65+/-12 pg/ml, control vs. fructose, P<0.05). Depressor responses to alpha(1)-adrenergic blockade with prasozin were augmented in fructose-fed mice. Using quantitative in situ hybridization, we found that Ang AT1a receptor and TH mRNA expression were significantly increased in the brainstem locus coeruleus. CONCLUSION: A high fructose diet in mice produced nocturnal hypertension and autonomic imbalance which may be related to activation of sympathetic and angiotensin systems.     

Sympathetic activity in the rat: effects of anaesthesia on noradrenaline kinetics

Noradrenaline (NA) kinetics represent an effective tool for evaluating the activity of the sympathetic system: thus plasma NA concentration, spillover rate (SOR) and metabolic clearance rate (MC) were measured in the rat. The dilution technique was adapted and validated: pithing that caused mechanical destruction of the spinal cord was shown to reduce drastically NA-SOR and plasma NA concentration with no effect on NA-MC. NA-SOR and plasma NA concentration were restored within their normal limits when 2.5 Hz electrical stimulation of the sympathetic roots was superimposed. Normal values of NA kinetics in non-anaesthetised normotensive 12-week-old rats are reported: NA-SOR=196.1+/-26.4 ng/kg/min, NA-MC=413.9+/-38.8 ml/kg/min and plasma NA=486+/-52 pg/ml. NA kinetic was investigated in response to anaesthesia, known to depress excitable tissues of the central nervous system and expected to depress the activity of the sympathetic system. When NA-SOR was significantly reduced during anaesthesia with either sodium pentobarbital or chloralose, plasma NA concentration was not changed because NA-MC was also reduced. Thus, plasma NA concentration can be a misleading marker of the sympathetic activity. The response of the sympathetic activity to four different anaesthetic agents is shown to be heterogeneous, ranging from inhibition to stimulation. Sodium pentobarbital anaesthesia was associated with a statistically significant reduction of both NA-SOR (105.6+/-14.1 ng/kg/min, P<0. 01) and NA-MC (239.3+/-18.7 ml/kg/min, P<0.001) while plasma NA was not changed (438+/-47 pg/ml). Chloralose reduced NA-SOR (101.6+/-20. 1 ng/kg/min, P<0.05) while ketamine did not (150.6+/-35.5 ng/kg/min, n.s.): both compounds reduced NA-MC (257.9+/-27.8 ml/kg/min, P<0.01 and 265.8+/-34.3 ml/kg/min, P<0.05, respectively). Diethyl ether was shown to increase both NA-SOR (472.2+/-111 ng/kg/min, P<0.05) and plasma NA concentration (1589+/-436 pg/ml, P<0.01), while NA-MC remained unchanged. Thus, any investigation of the activity of the sympathetic system in the anaesthetised rat has to take into account the specific effects related to the anaesthetic agent used.     

Heart rate variability response to mental arithmetic stress in patients with schizophrenia: autonomic response to stress in schizophrenia

BACKGROUND: The vulnerability-stress hypothesis is an established model of schizophrenia symptom formation. We sought to characterise the pattern of the cardiac autonomic response to mental arithmetic stress in patients with stable schizophrenia. METHODS: We performed heart rate variability (HRV) analysis on recordings obtained before, during, and after a standard test of autonomic function involving mental stress in 25 patients with DSM-IV schizophrenia (S) and 25 healthy individuals (C). RESULTS: Patients with schizophrenia had a normal response to the mental arithmetic stress test. Relative contributions of low-frequency (LF) HRV and high-frequency (HF) HRV influences on heart rate in patients were similar to controls both at rest (LF 64+/-19% (S) vs. 56+/-16% (C); HF 36+/-19% (S) vs. 44+/-16% (C), t=1.52, p=0.136) and during mental stress, with increased LF (S: 76+/-12%, C: 74+/-11%) and decreased HF (S: 24+/-12%, C: 26+/-11%) in the latter study condition. Whilst healthy persons recovered the resting pattern of HRV immediately after stress termination (LF 60+/-15%, HF 40+/-15%, F=18.5, p<0.001), in patients HRV remained unchanged throughout the observed recovery period, with larger LF (71+/-17%) and lower HF (29+/-17%) compared with baseline (F=7.3, p=0.013). CONCLUSIONS: Patients with schizophrenia exhibit a normal response to the mental arithmetic stress test as a standard test of autonomic function but in contrast with healthy individuals, they maintain stress-related changes of cardiac autonomic function beyond stimulus cessation.     

Vagal neurostimulation in patients with coronary artery disease

We tested the hypotheses that (1) progression of coronary artery disease (CAD) increases sympathetic inflow to the heart, thus impairing cardiac blood supply, and (2) reduced sympathetic tone improves cardiac microcirculation and ameliorates severity of anginal symptoms. Electrical irritation of the nerve auricularis--a sensitive ramus of the vagus nerve--provides a central sympatholytic action. Using this technique, we studied the effects of vagal neurostimulation (VNS) on hemodynamics, the content of atrial noradrenergic nerves and the microcirculatory bed of CAD patients. VNS was performed in the preoperative period of CAD patients with severe angina pectoris. The comparison groups consisted of untreated patients with CAD or Wolff-Parkinson-White syndrome. Atrial tissue of patients with this syndrome (n = 6); with effort angina (n = 14); with angina at rest (n = 10); and with severe angina treated with VNS (n = 8) contained the following volume percentages of noradrenergic nerves: 1.7+/-0.1%, 1.3+/-0.3%, 0.5+/-0.1% (p < 0.05 vs. the other groups) and 1.3+/-0.2%, respectively. In these groups, cardiac microcirculatory vessels (diameter, 10-20 microm) had the following densities: 2.7+/-0.2%, 3.4+/-0.2%, 2.0+/-0.4% (p < 0.05 vs. the other groups) and 3.3+/-0.3%, respectively. VNS treatment abolished angina at rest, decreased heart rate and blood pressure. It improved left ventricular ejection fraction from 50+/-1.5% to 58+/-1.0% (p < 0.05), also changing left ventricular diastolic filling. The ratio of time velocity integrals of the early (Ei) to late (Ai) waves increased from 1.07+/-0.12 to 1.65+/-0.17 after VNS (p < 0.05). In electrocardiograms of VNS-treated patients, QRS- and QT-duration were shortened. the PQ-interval did not change, but T-wave configuration improved. In the postoperative period, heart failure occurred in 90% of the control group. vs. 12% in patients treated with VNS (p < 0.05). We conclude that CAD is characterized by overactivity of sympathetic cardiac tone. Vagal stimulation reduced sympathetic inflow to the heart, seemingly via an inhibition of norepinephrine release from sympathetic nerves. VNS' sympatholytic/vagotonic action dilated cardiac microcirculatory vessels and improved left ventricular contractility in patients with severe CAD.     

Comparing Type D personality and older age as correlates of tumor necrosis factor-alpha dysregulation in chronic heart failure

Tumor necrosis factor-alpha (TNF-alpha) and its soluble receptors 1 (sTNFR1) and 2 (sTNFR2) have been shown to be implicated in the pathogenesis of chronic heart failure (CHF). Ageing is accompanied by increased plasma levels of pro-inflammatory cytokines. We hypothesized that Type D personality (joint tendency to experience negative emotions and to inhibit self-expression) and age may have similar pro-inflammatory effects in the context of CHF. Participants in this study were 130 consecutive outpatients with CHF (76% men); there were 70 relatively younger (or=60 years) patients. They all completed the 14-item Type D Scale (DS14); 43 patients (33%) had a Type D personality. A multivariate model of cytokine levels indicated an independent overall effect of both older age [F(1,128)=9.11, p=.003] and Type D personality [F(1,128)=8.28, p=.005]. Stratifying patients in age/personality subgroups showed that younger non-Type D patients had the lowest and older Type D patients the highest sTNFR1 and sTNFR2 levels (986+/-318 vs 1661+/-1128 pg/ml and 1838+/-777 vs 2823+/-1439 pg/ml, p<.0001). Importantly, the mean sTNFR1 level in younger Type D patients (1359+/-660 pg/ml) was equivalent to that in older non-Type D patients (1360+/-440 pg/ml, p=.99) who were on average 18 years older. Younger Type D and older non-Type D patients also had similar sTNFR2 levels (2406+/-1329 vs 2448+/-812 pg/ml, p=.88). Only older Type D patients had a higher mean TNF-alpha level as compared to patients who were younger or who were not Type D (5.4+/-2.9 vs 3.9+/-2.4 pg/ml, p=.008). A logistic regression model including sex, severity of CHF, systolic heart failure and ischemic etiology indicated that the combined risk category of older age or Type D was independently associated with substantially increased sTNFR1 and sTNFR2 levels. Hence, Type D personality was associated with increased TNF-alpha activity. This disease-promoting effect of Type D matched the pro-inflammatory effect of ageing.     

Autonomic dysfunction in multiple sclerosis is related to disease activity and progression of disability.

BACKGROUND: Autonomic dysfunction is frequently observed in patients with multiple sclerosis (MS) but the evolution over time and the relationship to clinical characteristics are not yet established. OBJECTIVES: We investigated the correlation of disease activity and progression of disability with composite scores of cardiovascular autonomic dysfunction and serum levels of catecholamines in a cross-sectional study of patients with clinically active and clinically stable MS. In a longitudinal study of clinically active MS patients, we performed cardiovascular reflex tests for up to 2 years. METHODS: Twenty-six patients with clinically active relapsing-remitting MS, age 33.0 +/- 7.3 years, and nine patients with clinically stable MS, age 41.3 +/- 10.9 were studied. Twenty-four healthy volunteers served as controls. Standard autonomic tests were repeated at 3, 6, 12, 18 and 24 months in 18 of the 26 active patients participating in a placebo-controlled trial with interferon-beta-1a. Parasympathetic dysfunction was assessed by heart rate response to the Valsalva manoeuvre, deep breathing and active change of posture, while sympathetic dysfunction was analysed by blood pressure response to active change of posture and to sustained handgrip, and by measuring levels of norepinephrine and epinephrine in serum obtained in the supine position. RESULTS: In the cross-sectional study, the number of patients with at least one abnormal sympathetic test was higher in the 'active' patient group (39%) than in healthy controls (8%, P< 0.02) or 'stable' patients (0%, P< 0.04), while no difference was seen in the parasympathetic score. Median catecholamine levels were significantly lower in 'active' MS patients than in those with stable disease (norepinephrine, 204 ng/l (interquartile range 158-310 ng/l) vs 363 ng/l (269-507 ng/l), P<0.02 and epinephrine, 23 ng/l (16-28 ng/l) vs 32 ng/l (24-107 ng/l), P<0.04). In the subgroup of patients studied longitudinally, parasympathetic but not sympathetic dysfunction increased slightly during the follow-up period, with a significant correlation to the increase in clinical disability (r=0.7, P<0.002). No difference was seen for any of the autonomic scores between patients treated with interferon-beta (n=12) and those receiving placebo (n=6). During acute exacerbations, only parasympathetic dysfunction tended to increase in parallel with a deterioration in the EDSS. CONCLUSIONS: Parasympathetic dysfunction was closely related to the progression of disability in patients with MS. In contrast, sympathetic dysfunction was associated to the clinical activity of MS. This is in line with previous observations suggesting that the autonomic nervous system may be intimately linked with the disordered immune regulation in MS.     

Schizophrenic patients who develop postoperative confusion have an increased norepinephrine and cortisol response to surgery

The purpose of this study was to investigate the relationship between postoperative confusion and the plasma norepinephrine (NE), adrenocorticotropin (ACTH) or cortisol response to surgery in schizophrenic patients. We studied 50 schizophrenic patients and 35 control patients who underwent orthopedic surgery and perioperatively measured plasma NE, ACTH and cortisol levels. Postoperative confusion during 72 h after the end of the operation occurred in 14 of 50 schizophrenic patients (28%) and in 2 of 35 control patients (6%). Plasma NE levels 15 min after skin incision, the next day, the second day and the third day after operation in schizophrenic patients with postoperative confusion (668.0 +/- 59.2, 522.0 +/- 96.5, 463.2 +/- 71.2 and 398.9 +/- 56.2 pg/ml, respectively) were significantly higher than those in schizophrenic patients without confusion (524.1 +/- 62.6, 342.4 +/- 38.6, 311.2 +/- 58.3 and 314.1 +/- 77.1 pg/ml, respectively). Plasma cortisol levels 15 min after the skin incision and the next and second days after operation in schizophrenic patients with postoperative confusion (23.6 +/- 3.2, 21.1 +/- 4.3 and 19.9 +/- 4.4 microg/dl, respectively) were significantly higher than those in schizophrenic patients without confusion (15.2 +/- 4.5, 14.3 +/- 5.1 and 13.8 +/- 3.8 microg/dl, respectively). In conclusion, the occurrence of postoperative confusion in schizophrenic patients is associated with an increase in plasma norepinephrine and cortisol levels during and after surgery.     

Sympathetic nervous system activity in panic disorder

To assess sympathetic nervous system (SNS) activity in panic disorder, arterialized venous norepinephrine (NE) and epinephrine (EPI) were measured in 10 patients and 10 age- and weight-matched controls. In addition, arterialized plasma NE kinetics were determined using a tritiated NE isotope dilution technique. There were no significant differences between patients and controls for resting, supine plasma NE levels, plasma NE appearance rate, plasma NE clearance, or plasma cortisol. However, plasma EPI levels were significantly higher in panic patients (103 +/- 23 vs. 33 +/- 16 pg/ml). Furthermore, there was a significant correlation between anxiety ratings and plasma EPI levels in panic disorder patients. These findings suggest that during the resting state, panic disorder is associated with a selective activation of the adrenomedullary component of the SNS.     

Th1 and Th2 serum cytokine profiles characterize patients with Hashimoto's thyroiditis (Th1) and Graves' disease (Th2)

OBJECTIVES: The aim of this study was to document the pattern of immune response, assessed by the measurement of both Th1 and Th2 serum cytokines, in patients suffering from autoimmune thyroid disease and toxic nodular goiter. METHODS: Both Th1 and Th2 serum cytokine levels were assayed in patients suffering from Graves' disease (GD, n = 25), Hashimoto's thyroiditis (HT, n = 21), and toxic nodular goiter (TNG, n = 7) and compared with corresponding levels of 25 healthy controls. Serum concentrations of IL-2, IL-1 beta, INF-gamma, TNF-alpha, IL-12, IL-15, IL-10, IL-18, IL-4 and IL-5 were assayed in fasting serum samples. RESULTS: It was found that patients with HT had higher IL-2 serum levels (12.16 +/- 0.66 pg/ml) compared to patients with TNG (9.25 +/- 0.84 pg/ml), GD (7.86 +/- 0.30 pg/ml) and controls (7.36 +/- 0.45 pg/ml; p = 0.0001), higher INF-gamma levels (7.60 +/- 0.33 pg/ml) compared to patients with TNG (5.77 +/- 0.55 pg/ml), GD (5.74 +/- 0.24 pg/ml) and controls (5.09 +/- 0.27 pg/ml; p = 0.0009), higher IL-12 levels (3.57 +/- 0.19 pg/ml) compared to patients with TNG (2.57 +/- 0.21 pg/ml), GD (2.48 +/- 0.13 pg/ml) and controls (2.59 +/- 0.23 pg/ml; p = 0.004), and higher IL-18 levels (27.52 +/- 1.75 pg/ml) compared to patients with TNG (18.71 +/- 2.24 pg/ml), GD (15.44 +/- 1.39 pg/ml) and controls (15.16 +/- 1.62 pg/ml; p = 0.0002). In contrast, patients with GD had higher serum levels of IL-4 (4.11 +/- 0.33 pg/ml) compared to patients with HT (3.0 +/- 0.16; p = 0.02) and higher IL-5 levels (4.22 +/- 0.30 pg/ml) compared to patients with TNG (3.21 +/- 0.58 pg/ml), HT (2.75 +/- 0.16 pg/ml) and controls (2.0 +/- 0.19 pg/ml; p = 0.0001). Patients had lower IL-1 beta serum levels (TNG 2.45 +/- 0.20, HT 2.52 +/- 0.14, GD 2.68 +/- 0.12 pg/ml) compared to controls (3.6 +/- 0.20 pg/ml; p = 0.008). CONCLUSIONS: The above findings suggest that a Th1 pattern of immune response characteristic of cellular immunity is dominant in HT, whereas the predominance of Th2 cytokines in GD indicates a humoral pattern of immune reaction.     

Catecholamine metabolism in kinky hair disease

Kinky hair disease is a progressive neurologic disease associated with decreased copper absorption. Because dopamine-beta-hydroxylase, an essential enzyme in norepinephrine biosynthesis, is copper-dependent, we studied norepinephrine metabolism in vivo in 5 affected children. Patients with kinky hair disease had decreased plasma norepinephrine concentrations (196 +/- 25 pg/ml) in comparison to control patients (325 +/- 20 pg/ml, p less than 0.001). The ratio of total urinary norepinephrine metabolites to total dopamine metabolites was 0.25 +/- 0.04 in kinky hair patients and 0.52 +/- 0.03 in controls p less than 0.001). These data indicate that dopamine-beta-hydroxylation in vivo is decreased in patients with kinky hair disease; however, there was no correlation between serum copper concentration and catecholamine abnormality.     

Quantitative autonomic testing in the management of botulism

Even with mild neurological signs, patients with botulism frequently complain of autonomic symptoms. This study aimed at the evaluation of sudomotor and cardiovascular reflex functions by quantitative autonomic testing (QAT), which may identify patients with autonomic involvement but otherwise benign clinical presentation. Five patients with food-borne botulism were subjected to a structured questionnaire on autonomic symptoms, cardiac and neurological examination, and QAT after a median of 2 weeks (baseline) and 12 weeks (follow-up) post intoxication. For calculation of haemodynamic and cardiovascular autonomic parameters, we used the Task Force^® Monitor (Version 2.1, CNSystems, Graz, Austria). Cardiovagal function was assessed by Ewing’s test battery. Autonomic complaints were more pronounced than neurological symptoms. Baseline tests revealed widely abnormal sudomotor function and marked impairment of heart rate variation and blood pressure response to standing. Prominent features of cardiovascular failure were high resting heart rate, supine hypertension, orthostatic hypotension, and impaired baroreflex function. Three patients reported inability to keep up with their routine amount of physical work. Based on the baseline QAT results, these three patients were instructed to engage in physical activity but avoid physical strain until there was considerable improvement. On follow-up, fatigue was the most frequent residual complaint, sympathetic skin responses were present, and cardiovascular QAT results were significantly improved and did not differ from those of ten control subjects. QAT identified autonomic involvement in botulism patients with otherwise benign neurological presentation. Comprehensive evaluation of autonomic failure may provide useful information for the management of botulism.