Gemtuzumab ozogamicin plus midostaurin in combination with standard '7 + 3' induction therapy in newly diagnosed AML: Results from the SAL-MODULE phase I study.

We conducted a phase I trial in newly diagnosed acute myeloid leukaemia (AML) to investigate the combination of two novel targeted agents, gemtuzumab ozogamicin (GO) and midostaurin, with intensive chemotherapy in FLT3-mutated AML and CBF leukaemia. Three dose levels of midostaurin and one to three sequential doses of 3 mg/m2 GO in combination with '7 + 3' induction were evaluated. Based on safety findings in 12 patients, our results show that 3 mg/m2 GO on Days 1 + 4 and 100 mg midostaurin on Days 8-21 can be safely combined with IC in newly diagnosed AML.

Adrenomedullary function, obesity and permissive influences of catecholamines on body mass in patients with chromaffin cell tumours.

BACKGROUND: Obesity-associated activation of sympathetic nervous outflow is well documented, whereas involvement of dysregulated adrenomedullary hormonal function in obesity is less clear. This study assessed relationships of sympathoadrenal function with indices of obesity and influences of circulating catecholamines on body mass. METHODS: Anthropometric and clinical data along with plasma and 24-h urine samples were collected from 590 volunteers and 1368 patients tested for phaeochromocytoma and paraganglioma (PPGL), among whom tumours were diagnosed in 210 individuals. RESULTS: Among patients tested for PPGL, those with tumours less often had a body mass index (BMI) above 30 kg/m2 (12 vs. 31%) and more often a BMI under 25 kg/m2 (56 vs. 32%) than those without tumours (P < 0.0001). Urinary outputs of catecholamines in patients with PPGL were negatively related to BMI (r = -0.175, P = 0.0133). Post-operative weight gain (P < 0.0001) after resection of PPGL was positively related to presurgical tumoural catecholamine output (r = 0.257, P = 0.0101). Higher BMI in men and women and percent body fat in women of the volunteer group were associated with lower plasma concentrations and urinary outputs of adrenaline and metanephrine, the former indicating obesity-related reduced adrenaline secretion and the latter obesity-related reduced adrenomedullary adrenaline stores. Daytime activity was associated with substantial increases in urinary adrenaline and noradrenaline excretion, with blunted responses in obese subjects. CONCLUSIONS: The findings in patients with PPGL support an influence of high circulating catecholamines on body weight. Additional associations of adrenomedullary dysfunction with obesity raise the possibility of a permissive influence of the adrenal medulla on the regulation of body weight.

Chronic depression symptoms and salivary NOx are associated with retinal vascular dysregulation: The SABPA study.

BACKGROUND: Depression has been associated with impaired nitric oxide (NO)-mediated vasodilation and vascular dysregulation (VD). Whether depression and NO levels will disturb retinal haemodynamics is not clear. OBJECTIVES AND METHODS: Associations between the retinal vasculature, diastolic ocular perfusion pressure (DOPP) as measure of hypoperfusion, NO metabolites (NOx) and depression symptoms were assessed. Chronic VD risk markers [depression symptoms (Patient Health Questionnaire/PHQ-9 ≥ 10) and 24 h pulse pressure] were determined in a bi-ethnic cohort (n = 313; 48.6 ± 9 years; 53.9% men). At 3 year follow-up, retinal vessel calibre and retinopathy signs were quantified from digital images. Salivary NOx was obtained pre- and post-flicker light-induced provocation (FLIP). DOPP was defined as diastolic blood pressure minus intraocular pressure. RESULTS: Chronic VD risk was evident in Blacks opposed to acute risk in Whites (P < 0.05). At follow-up, retinopathy (Blacks 60.4%/Whites 39.6%), lower pre-FLIP (µM) and higher post-FLIP NOx (changes from baseline, %), arteriolar narrowing and wider venular calibre values were evident in Blacks compared to Whites, independent of confounders. A wider venular calibre, an index of stroke risk, was associated with chronic depression symptoms [cut point 248 MU: Area under the curve 0.61 (95% CI: 0.51, 0.72); 71% sensitivity; 55% specificity] as well as with hypoperfusion in the Blacks. In this group, arteriolar narrowing was associated with hypoperfusion; and attenuated arteriolar dilation with increased post-FLIP NOx responses. CONCLUSIONS: Chronic depression symptoms may alter NO regulation and facilitate VD. NO-mediated vasoconstriction presumably impeded perfusion, retinal haemodynamics and -remodelling; potentiating stroke risk in Blacks.

Comparison of baroreflex sensitivity estimated from ECG R-R and inter-systolic intervals obtained by finger plethysmography and radial tonometry.

Spontaneous BRS estimates may considerable vary according to the technique of blood pressure and heart rate assessment. To optimise and standardise BRS estimation for clinical use we evaluated possible differences between spontaneous BRS indices estimated from either finger plethysmography or radial tonometry. Forty-five healthy volunteers underwent simultaneous recordings of electrocardiogram, finger plethysmography and radial tonometry in supine position and during 60° head-up tilt. BRS was computed by spectral analysis from either R-R time series and/or arterial pressure pulse. Radial tonometry generated higher mean BRS estimates than finger plethysmography. The difference decreased upon postural change from supine to upright. In the upright position, BRS estimates based on R-R interval proved to be generally lower compared to BRS indices estimated from arterial pressure pulse. The ratio of low-to-high-frequency power of inter-systolic interval and systolic blood pressure from tonometry was lower than that from plethysmography in supine and approximated in upright position. Spectral parameters of inter-systolic interval and R-R interval did not differ in supine but diverged in upright position. Changes of spectral parameters were most pronounced in R-R interval. Arterial pressure pulse is adequate for estimation of BRS under resting conditions but it may distort BRS estimates under physical load. We, therefore, recommend using an ECG signal for BRS estimation especially in non-stationary conditions.

Insulin is a key determinant of elevated retinal arteriolar flicker response in insulin-resistant individuals.

AIMS/HYPOTHESIS: Insulin may link metabolic disorders to retinal microvascular pathology. The aim of the present study was to investigate the impact of early insulin resistance on retinal microcirculation. METHODS: Retinal diameter responses to flicker-light stimulation were investigated in 81 clinically healthy participants (32 ± 6 years [mean ± SD], 59% women) who were recruited according to their BMI. All participants underwent an OGTT and euglycaemic-hyperinsulinaemic clamp (40 mU/m(2) · min(-1) insulin dose). After stratification by low and high insulin sensitivity based on a clamp-derived glucose disposal rate of ≤ or >4.9 mg/kg body mass, respectively, baseline retinal diameters and their relative changes to flicker stimulation were compared while controlling for mean arterial pressure, BMI and sex. RESULTS: The arterial vasodilator response at the end of flicker stimulation (p = 0.044) and the area under the arterial reaction curve during flicker stimulation (p = 0.015) were significantly higher in individuals with low vs high insulin sensitivity. Vasodilatory responses of retinal veins to flicker stimulation and baseline retinal diameters did not differ between insulin-sensitive and insulin-resistant participants (p > 0.05). In a stepwise linear regression analysis, fasting insulin remained the only predictor of the arterial vasodilator response to flicker-light (p < 0.01). Waist circumference also contributed, although to a lesser extent, to the arterial vasodilator response (p = 0.023). CONCLUSIONS/INTERPRETATION: Insulin sensitivity is an important determinant of retinal microvascular function. We propose that the elevated arterial flicker response in insulin-resistant states is a result of higher circulating insulin levels.

Local endothelial dysfunction does not affect global endothelial function.

BACKGROUND: The purpose of this study was to evaluate two alternative non-invasive techniques for assessment of endothelial function in adults with special focus on their ability to monitor acute changes. PATIENTS AND METHODS: Twenty-five clinically healthy men (mean age 24 ± 2 years) underwent endothelial function measurements twice in fasting state and twice after experimental induction of transient endothelial dysfunction by oral application of 0.1g/kg L-methionine and by ingestion of 500 ml whipped cream (30 % fat), respectively. Microvascular vasodilator responses to flickering-light by retinal vessel analysis and vascular responses to inhaled salbutamol by pulse wave analysis were assessed at each occasion. Ultrasound based flow-mediated dilation (FMD) was used as reference method. RESULTS: Transient endothelial dysfunction in response to acute hyperlipidaemia and hyperhomocysteinaemia was verified by blunted brachial responses to hyperaemia. Retinal vessel analysis demonstrated significantly impaired flicker-responses of retinal vessels to both challenges depending on the vessel type. Pulse wave analysis did not show any significant changes in salbutamol responses. Reproducibility of retinal vessel analysis was comparable to FMD and slightly better than pulse wave analysis. CONCLUSIONS: Acute changes in endothelial function can be monitored by retinal vessel analysis with comparable reproducibility as FMD. Salbutamol based pulse wave analysis is currently unsuited to detect endothelial dysfunction in serial measurements.

Effects of acute and chronic stress on the L-arginine nitric oxide pathway in black and white South Africans: the sympathetic activity and ambulatory blood pressure in Africans study.

OBJECTIVE: This study investigated the impact of stress on effectors of the L-arginine/nitric oxide (NO) system including the endogenous inhibitor asymmetric dimethylarginine (ADMA). METHODS: Black (n = 168) and white (n = 206) South African teachers were exposed to a mental and a physical stressor for 1 minute, respectively. Serum samples for determination of l-arginine, NO metabolites, ADMA, and symmetric dimethylarginine (SDMA) were obtained at rest and during stress exposure. Perception of task stressfulness was assessed on a 7-point Likert scale, and psychological distress was estimated by the General Health Questionnaire. RESULTS: Black South Africans exhibited higher resting levels of NO metabolites (adjusted mean [standard error of the mean] = 11.3 [1.3] versus 3.9 [1.1] µmol/l, p < .001) but lower circulating ADMA (0.62 [0.02] versus 0.70 [0.02] µmol/l, p = .004) and SDMA (0.41 [0.01] versus 0.53 [0.01] µmol/l, p < .001) than did white South Africans. Ethnicity-by-psychological distress interaction was observed for resting levels of ADMA (p = .002), SDMA (p = .038), and L-arginine (p = .048). Ethnic differences in responses to experimental stress were evident for NO metabolites (blacks versus whites: 5.94 [1.55] versus -0.74 [1.25] µmol/l, p = .004) and SDMA (blacks versus whites: -0.02 [0.01] versus 0.02 [0.01] µmol/l, p = .004). Ethnicity-by-psychological distress interaction for stress responses was found for l-arginine/ADMA ratio (p = .027). CONCLUSIONS: The l-arginine/NO system is affected by psychosocial distress with higher susceptibility in black South Africans. This interaction may contribute to the higher cardiovascular disease risk in black South Africans.

Trigonometric regressive spectral analysis: an innovative tool for evaluating the autonomic nervous system.

Biological rhythms, describing the temporal variation of biological processes, are a characteristic feature of complex systems. The analysis of biological rhythms can provide important insights into the pathophysiology of different diseases, especially, in cardiovascular medicine. In the field of the autonomic nervous system, heart rate variability (HRV) and baroreflex sensitivity (BRS) describe important fluctuations of blood pressure and heart rate which are often analyzed by Fourier transformation. However, these parameters are stochastic with overlaying rhythmical structures. R-R intervals as independent variables of time are not equidistant. That is why the trigonometric regressive spectral (TRS) analysis--reviewed in this paper--was introduced, considering both the statistical and rhythmical features of such time series. The data segments required for TRS analysis can be as short as 20 s allowing for dynamic evaluation of heart rate and blood pressure interaction over longer periods. Beyond HRV, TRS also estimates BRS based on linear regression analyses of coherent heart rate and blood pressure oscillations. An additional advantage is that all oscillations are analyzed by the same (maximal) number of R-R intervals thereby providing a high number of individual BRS values. This ensures a high confidence level of BRS determination which, along with short recording periods, may be of profound clinical relevance. The dynamic assessment of heart rate and blood pressure spectra by TRS allows a more precise evaluation of cardiovascular modulation under different settings as has already been demonstrated in different clinical studies.

Nocturnal blood pressure, 3-methoxy-4-hydroxyphenylglycol and carotid intima-media thickness: The SABPA study.

BACKGROUND: Research demonstrated a significant relationship between elevated nocturnal blood pressure and sympathetic hyperactivity. The study aimed to investigate possible associations between norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), nocturnal BP and carotid intima-media thickness (CIMT) in urban African and Caucasian men. METHODS: The study included 82 African and 100 Caucasian male teachers, aged 33-56 years, recruited in the North-West Province, South Africa. Ambulatory BP and fasting saliva and blood samples were collected. B-mode ultrasound images were obtained to determine CIMT. RESULTS: Despite higher usage of anti-hypertensive medication usage (p=0.039), a large number of the African men were nocturnal hypertensives (75, 61%). The nocturnal systolic blood pressure (SBP) (p<0.001), diastolic blood pressure (DBP) (p<0.001) and heart rate (p<0.001) of the African men were higher. After stratifying groups into only nocturnal hypertensives the trend was the same (SBP p<0.001; DBP p<0.001; heart rate p=0.058). In the African and Caucasian men, CIMT was linearly predicted by SBP (ß=0.33, p<0.001) and DBP (ß=0.24, p=0.016) respectively, but not MHPG. CONCLUSION: No associations were firstly demonstrated between MHPG as sympathetic activity marker and CIMT or secondly, between MHPG and nocturnal blood pressure. Novel findings of elevated nocturnal BP evidently seem to promote structural vascular disease in urban African and Caucasian men.

Baroreceptor sensitivity, cardiovascular responses and ECG left ventricular hypertrophy in men: the SABPA study.

AIM. Research has shown a significant relationship between hypertension and attenuated baroreceptor sensitivity (BRS), which in turn reflects alterations of autonomic control of the cardiovascular system. The objective of this study was to compare the BRS of African and Caucasian men and determine possible associations with blood pressure and left ventricular hypertrophy. MATERIALS AND METHODS. Participants included African (n = 82) and Caucasian (n = 100) male teachers, aged between 20 and 65 years, recruited in the North-West Province, South Africa. Ambulatory blood pressure monitoring was conducted for a 22-23-h period and, thereafter, cardiovascular parameters were recorded with a Finometer and 12-lead ECG during rest and while challenging the cardiovascular system with the cold pressor and Stroop color?word conflict tests. Spontaneous BRS was calculated as well as the Cornell product [marker of left ventricular hypertrophy (LVH)]. RESULTS. The African men had significantly lower BRS stress responses. Attenuated BRS coupled to an ?-adrenergic response pattern predicted elevation of blood pressure in the African men. BRS reduction did not prove to be a significant predictor of LVH. CONCLUSION. Lower BRS, especially during stress, may pose a significant health threat for African men regarding earlier development or promotion of α -adrenergic-driven hypertension and greater risk for cardiovascular disease.

Arterial stiffness profiles: investigating various sections of the arterial tree of African and Caucasian people.

In Africans, arterial stiffness progression seems more pronounced compared to Caucasians. We compared the arterial stiffness profiles of different age groups and focused on muscular arteries and two more central arterial segments in African and Caucasian people from South Africa. In African (N = 374) and Caucasian (N = 376) participants (20-70 years), we measured carotid-radial (C-R) and carotid-dorsalis pedis (C-DP) pulse wave velocity (PWV) and aortic characteristic impedance (Zao). Major findings were that normotensive and high-normal/hypertensive (HT) Caucasians indicated increased trends of C-R PWV with aging (P = .029 and P = .067), not seen in the African groups (P = .122 and P = .526). Both ethnic groups showed significant increases of C-DP PWV and Zao with aging. High-normal/hypertensive Africans had significantly stiffer arteries than hypertensive Caucasians for almost all age groups, and for all stiffness measures. African C-R PWV correlated significantly with blood pressure (BP), but not with age. Opposite results were observed for Caucasians. In conclusion, the stiffness of muscular arteries is already elevated in young Africans, in both those with normal or elevated BP. This is possibly due to an earlier deterioration during childhood, or perhaps already present from birth. Also, in Caucasians stiffness seems more age-related, while in Africans it seems to be more pressure-related.

Comprehensive autonomic assessment does not differentiate between Parkinson's disease, multiple system atrophy and progressive supranuclear palsy.

Differential diagnosis of parkinsonian syndromes is a major challenge in movement disorders. Dysautonomia is a common feature but may vary in clinical severity and onset. The study attempted to find a pattern of autonomic abnormalities discriminative for patients with different parkinsonian syndromes. The cross-sectional study included 38 patients with multiple system atrophy (MSA), 32 patients with progressive supranuclear palsy (PSP), 26 patients with idiopathic Parkinson's disease (IPD) and 27 age-matched healthy controls. Autonomic symptoms were evaluated by a standardized questionnaire. The performance of patients and controls was compared on five autonomic function tests: deep breathing, Valsalva manoeuvre, tilt-table testing, sympathetic skin response, pupillography, and 24-h ambulatory blood pressure monitoring (ABPM). Disease severity was significantly lower in IPD than PSP and MSA. Except for pupillography, none of the laboratory autonomic tests distinguished one patient group from the other alone or in combination. The same was observed on the questionnaire. Receiver operating characteristic curve revealed discriminating performance of pupil diameter in darkness and nocturnal blood pressure change. The composite score of urogenital and vasomotor domains significantly distinguished MSA from IPD patients but not from PSP. Our study supports the observation that even mild IPD is frequently indistinguishable from more severe MSA and PSP. Thus, clinical combination of motor and non-motor symptoms does not exclusively point at MSA. Pupillography, ABPM and the questionnaire may assist in delineating the three syndromes when applied in combination.

Autonomic function and cerebral autoregulation in patients undergoing carotid endarterectomy.

BACKGROUND: Carotid endarterectomy (CEA) is the first-line treatment in severe carotid stenosis to prevent stroke. Because of methodological limitations, the acute impact of CEA on baroreflex function and cerebral autoregulation is not well defined and was therefore investigated by applying a novel algorithm. METHODS AND RESULTS: Systemic arterial blood pressure, ECG and respiration during metronomic breathing and Valsalva maneuver were continuously recorded in 18 patients with carotid stenosis before and after CEA, and in 10 healthy controls. Baroreflex sensitivity, frequency spectra of RR intervals and indices for cerebral autoregulation were evaluated by trigonometric regressive spectral analysis. Compared with the controls, patients had impaired baroreflex sensitivity. Baroreflex sensitivity and frequency spectra were not changed by CEA. Cerebral autoregulation of patients with carotid stenosis as calculated by phase shift was reduced compared with controls but it improved significantly after CEA. Improvement of cerebral autoregulation was independent of changes in cerebral blood flow velocity. CONCLUSIONS: Baroreflex sensitivity and cerebral autoregulation are impaired in patients with carotid stenosis, conferring a high stroke risk. CEA improves cerebral autoregulation, but does not affect baroreflex sensitivity. For further risk reduction, interventional approaches targeting baroreflex function need to be considered.

Sudomotor Testing of Diabetes Polyneuropathy.

Objective: The performance of the Sudoscan technology for diagnosing diabetic polyneuropathy (DPN) was evaluated against the quantitative sudomotor axon reflex test (QSART). Furthermore, the association of Sudoscan with two clinical neuropathy scoring systems was evaluated. Methods: Forty-seven patients with type 2 diabetes (20 without DPN, 27 with DPN) and 16 matched controls were examined for neuropathic symptoms and for the extent of sensory deficits. Sweat latency and volume by QSART and the skin electrochemical conductance (ESC) by Sudoscan were measured. Results: The feet and hand ESC was significantly lower in patients with DPN as compared to controls. Patients with DPN had also lower hand ESC than patients without DPN. Sensitivity and specificity of feet and hand ESC for detecting DPN were 70/85% and 53/50% respectively. QSART could not differentiate between the three groups. ESC was inversely related to neuropathic symptoms and sensory impairment. ESC was significantly correlated with sensory impairment and pain. Conclusions: Sudoscan shows a good performance in detecting subjects with DPN and it correlates well with clinical signs and symptoms of neuropathy. Significance: This study provides evidence that Sudoscan has high potential to be used as screening tool for DPN and possibly also for small fiber neuropathy in diabetic patients. HIGHLIGHTS - The sudomotor function test Sudoscan shows a good performance to detect diabetes peripheral neuropathy.- Sudoscan measures significantly correlate with clinical signs and symptoms of neuropathy.- The Sudoscan technology may help to secure clinical diagnosis of small fiber neuropathy.

Ethnic differences in C-peptide secretion but not in non-esterified fatty acid metabolism in pre-menopausal women with and without abdominal obesity.

The present study aimed to reveal racial differences in the metabolic pattern of C-peptide and non-esterified fatty acids (NEFA), and in their associations with cardiovascular measures in healthy urban African (102) and Caucasian women (115) from South Africa. An oral glucose tolerance test was performed with measurements before and at 30, 60, 90 and 120min. Various cardiovascular parameters and blood lipids were assessed. Statistical analyses were done in a sub-sample of pre-menopausal women. Fasting C-peptide and hepatic insulin extraction were significantly higher in lean African women compared to their Caucasian counterparts, with no racial differences between women with abdominal obesity. Postchallenge C-peptide response and hepatic insulin extraction were significantly higher in Caucasians with abdominal obesity. There were no racial differences in insulin sensitivity and resistance. Despite different associations of C-peptide and NEFA with cardiovascular measures between the ethnicities both showed significant positive correlations with triglycerides. Increased fasting C-peptide levels and unfavorable associations of C-peptide and NEFA with triglycerides and cardiovascular measures implicate a higher cardiovascular risk in lean African women only. This may be of importance for the development of hypertension in this population group.

Troponin T release is associated with silent myocardial ischaemia in black men: The SABPA Study.

Background High sensitivity cardiac troponin T (hs-cTnT) is a validated marker of myocardial damage and may reflect the degree of silent myocardial ischaemia (SMI) and ventricular strain. Our aim was to compare hs-cTnT levels in black and white South Africans taking SMI into consideration. We further explored the capability of hs-cTnT to predict the presence of compensatory systolic hypertension in this South African cohort. Methods A bi-ethnic sex cohort ( n = 404) with similar socioeconomic status (198 black participants and 206 white participants, aged 20-65 years) participated in this target population study where 24 h ambulatory blood pressure, electrocardiogram and overnight fasting cardiometabolic variables were measured. Results Hypertension, higher glycated haemoglobin levels and more frequent and longer SMI events were observed more often in the black participants. Multivariate linear regression analysis showed positive associations between SMI events [Adj. R2 = 0.19; ß 0.35 (0.08-0.62); p < 0.01], SMI event maximum duration [Adj. R2 = 0.17, ß 0.43 (0.16-0.70), p < 0.01], SMI total duration [Adj. R2 = 0.12; ß 0.37 (0.10; 0.65), p = 0.05] and hs-cTnT in black males only.] A lower hs-cTnT cut-point ≥4.2 pg/ml for 24 h systolic hypertension was predicted in the black participants compared with ≥5.6 pg/ml in the white participants (area under the curve 0.66-67 (95% CI: 0.57-0.75), p < 0.001) with a respective sensitivity/specificity of 64/68% and 61/71%. Conclusions hs-cTnT may be a potential marker of SMI in the prediction of systolic blood pressure increases, as well as clusters of risk factors for cardiovascular disease. Ethnic- and possibly sex-specific references values for hs-cTnT should be considered for risk stratification.

Modulation of Cardiac Autonomic Function by Fingolimod Initiation and Predictors for Fingolimod Induced Bradycardia in Patients with Multiple Sclerosis.

Objective: It is well-known that initiation of fingolimod induces a transient decrease of heart rate. However, the underlying cardiac autonomic regulation is poorly understood. We aimed to investigate the changes of autonomic activity caused by the first dose of fingolimod using a long-term multiple trigonometric spectral analysis for the first time. In addition, we sought to use the continuous Holter ECG recording to find predictors for fingolimod induced bradycardia. Methods: Seventy-eight patients with relapsing-remitting multiple sclerosis (RRMS) were included. As a part of the START study (NCT01585298), continuous electrocardiogram was recorded before fingolimod initiation, and until no <6 h post medication. Time domain and frequency domain heart rate variability (HRV) parameters were computed hourly to assess cardiac autonomic regulation. A long-term multiple trigonometric regressive spectral (MTRS) analysis was applied on successive 1-h-length electrocardiogram recordings. Decision tree analysis was used to find predictors for bradycardia following fingolimod initiation. Results: Most of the HRV parameters representing parasympathetic activities began to increase since the second hour after fingolimod administration. These changes of autonomic regulations were in accordance with the decline of heart rate. Baseline heart rate was highly correlated with nadir heart rate, and was the only significant predicting factor for fingolimod induced bradycardia among various demographic, clinical and cardiovascular variables in the decision tree analysis. Conclusions: The first dose application of fingolimod enhances the cardiac parasympathetic activity during the first 6 h post medication, which might be the underlying autonomic mechanism of reduced heart rate. Baseline heart rate is a powerful predictor for bradycardia caused by fingolimod.

Subthalamic nucleus stimulation and levodopa modulate cardiovascular autonomic function in Parkinson's disease.

We aimed to explore the effects of bilateral subthalamic nucleus stimulation and levodopa on cardiovascular autonomic function in Parkinson's disease. Twenty-six Parkinson's disease patients with bilateral subthalamic nucleus stimulation in a stable state were tested under stimulation off and dopaminergic medication off (OFF-OFF), stimulation on and dopaminergic medication off (ON-OFF), and stimulation on and medication (levodopa) on (ON-ON) conditions by recording continuously blood pressure, ECG, and respiration at rest, during metronomic deep breathing, and head-up tilt test. Thirteen patients were diagnosed as orthostatic hypotension by head-up tilt test. Baroreflex sensitivity and spectral analyses were performed by trigonometric regressive spectral analysis. Subthalamic nucleus stimulation and levodopa had multiple influences. (1) Systolic blood pressure during tilt-up was reduced by subthalamic nucleus stimulation, and then further by levodopa. (2) Subthalamic nucleus stimulation and levodopa had different effects on sympathetic and parasympathetic regulations in Parkinson's disease. (3) Levodopa decreased baroreflex sensitivity and RR interval only in the orthostatic hypotension group, and had opposite effects on the non-orthostatic hypotension group. These findings indicate that subthalamic nucleus stimulation and levodopa have different effects on cardiovascular autonomic function in Parkinson's disease, which are modulated by the presence of orthostatic hypotension as well.

Soy-isoflavone-enriched foods and markers of lipid and glucose metabolism in postmenopausal women: interactions with genotype and equol production.

BACKGROUND: The hypocholesterolemic effects of soy foods are well established, and it has been suggested that isoflavones are responsible for this effect. However, beneficial effects of isolated isoflavones on lipid biomarkers of cardiovascular disease risk have not yet been shown. OBJECTIVE: The objective was to investigate the effects of isolated soy isoflavones on metabolic biomarkers of cardiovascular disease risk, including plasma total, HDL, and LDL cholesterol; triacylglycerols; lipoprotein(a); the percentage of small dense LDL; glucose; nonesterified fatty acids; insulin; and the homeostasis model assessment of insulin resistance. Differences with respect to single nucleotide polymorphisms in selected genes [ie, estrogen receptor alpha (XbaI and PvuII), estrogen receptor beta (AluI), and estrogen receptor beta(cx) (Tsp509I), endothelial nitric oxide synthase (Glu298Asp), apolipoprotein E (Apo E2, E3, and E4), cholesteryl ester transfer protein (TaqIB), and leptin receptor (Gln223Arg)] and with respect to equol production were investigated. DESIGN: Healthy postmenopausal women (n = 117) participated in a randomized, double-blind, placebo-controlled, crossover dietary intervention trial. Isoflavone-enriched (genistein-to-daidzein ratio of 2:1; 50 mg/d) or placebo cereal bars were consumed for 8 wk, with a wash-out period of 8 wk before the crossover. RESULTS: Isoflavones did not have a significant beneficial effect on plasma concentrations of lipids, glucose, or insulin. A significant difference between the responses of HDL cholesterol to isoflavones and to placebo was found with estrogen receptor beta(cx) Tsp509I genotype AA, but not GG or GA. CONCLUSIONS: Isoflavone supplementation, when provided in the form and dose used in this study, had no effect on lipid or other metabolic biomarkers of cardiovascular disease risk in postmenopausal women but may increase HDL cholesterol in an estrogen receptor beta gene-polymorphic subgroup.