Ovariectomy increases vascular calcification via the OPG/RANKL cytokine signalling pathway

Background Observational studies suggest a strong relationship between menopause and vascular calcification. Receptor activator of nuclear factor‐κΒ ligand (RANKL) and osteoprotegerin (OPG) are critical regulators of bone remodelling and modulate vascular calcification. We assessed the hypothesis that ovariectomy increases vascular calcification via the OPG/RANKL axis. Materials and methods Age‐matched sexually mature rabbits were randomized to ovariectomy (OVX, n = 12) or sham procedure (SHAM, n = 12). One month post‐procedure, atherosclerosis was induced by 15 months 0·2%‐cholesterol diet and endothelial balloon denudations (at months 1 and 3). Aortic atherosclerosis was assessed in vivo by magnetic resonance imaging (MRI) at months 9 and 15. At sacrifice, aortas were harvested for ex vivo microcomputed tomography (µCT) and molecular analysis of the vascular tissue. Results Vascular calcification density and calcific particle number were significantly greater in OVX than SHAM (8·4 ± 2·8 vs. 1·9 ± 0·6 mg cm^?3, P = 0·042, and 94 ± 26 vs. 33 ± 7 particles cm^?3, P = 0·046, respectively). Calcification morphology, as assessed by the arc angle subtended by the largest calcific particle, showed no difference between groups (OVX 33 ± 7° vs. SHAM 33 ± 5°, P = 0·99). By Western blot analysis, OVX increased the vascular OPG:RANKL ratio by 66%, P = 0·029, primarily by decreasing RANKL (P = 0·019). At month 9, MRI demonstrated no difference in atheroma volume between OVX and SHAM, and no significant change was seen by the end of the study. Conclusions In contrast to bone, vascular OPG:RANKL ratio increased in response to ovariectomy with a corresponding fourfold increase in arterial calcification. This diametrical organ‐specific response may explain the comorbid association of osteoporosis with calcifying atherosclerosis in post‐menopausal women.     

Cardiac troponin I and ventricular arrhythmia in patients with chronic heart failure

Background Both detectable serum cardiac troponin I (cTnI) and ventricular dysrhythmias are common in patients with chronic heart failure (CHF) and are paralleled with the severity of the CHF. However, the relationship between serum cTnI and ventricular arrhythmia severity in patients with CHF remains unknown; the mechanism of the ventricular arrhythmia in the CHF patients also remains unclear. Materials and methods The study group included 218 patients with CHF who had cTnI assay drawn at the time of initial presentation. Patients with acute myocardial infarction or myocarditis were excluded from the analysis. The patients were divided into two groups: cTnI‐positive with serum cTnI > 0·5 ng mL^?1 (n = 98) and cTnI‐negative with serum cTnI ≤ 0·5 ng mL^?1 (n = 120). The severity of ventricular dysrhythmias was assessed by 24‐h Holter monitoring, using prospectively defined measures of ventricular arrhythmic burden. Results Prevalence of risk factors for ventricular dysrhythmias was equal in both groups. All measures of ventricular ectopy were much higher in patients of the cTnI‐positive groups. Mean hourly ventricular pairs (13·59 ± 10·3 vs. 11·1 ± 6·01, P = 0·027), mean hourly repetitive ventricular beats (26·01 ± 13·67 vs. 22·01 ± 13·56, P = 0·032), and the frequency of ventricular tachycardia episodes per 24 h (12·54 ± 16·68 vs. 7·68 ± 11·54, P = 0·012) were higher in patients with detectable cTnI levels. After inclusion of clinical variables and drug therapies in a multivariate analysis, the positive relationship between cTnI and the frequency of ventricular pairs (P = 0·03), repetitive ventricular beats (P = 0·037), and ventricular tachycardia (P = 0·03) remained independent. In multivariate logistic regression, the risk of developing ventricular tachycardia was higher in patients with detectable cTnI levels with an adjusted odds ratio (OR) of 2·31 (95% CI, 1·22–2·65, P = 0·003). Conclusions In patients with CHF, serum cTnI is closely related to increased occurrence of ventricular dysrhythmias and could identify a subgroup of patients with ventricular tachycardia. The minimal myocardial injury detected by serum cTnI might be the abnormal substrate for ventricular dysrhythmias.     

WNK4 regulates airway Na+ transport: study of familial hyperkalaemia and hypertension

Background WNK [With No K (lysine)] kinases are essential for regulation of blood pressure and potassium homeostasis. WNK4 expression was recently found not only in the distal nephron but also in chloride‐transporting epithelia. To establish a physiological role for this distribution we studied patients with familial hyperkalaemia and hypertension (FHH), [pseudohypoaldosteronism type II (PHAII)], which is caused by mutations in WNK4. Design Measurement of nasal potential difference (NPD) and sweat electrolytes were performed in controls, in six subjects with FHH and ten subjects with cystic fibrosis (CF). Results Basal NPD was higher in FHH compared with controls (n = 20): 22·8 ± 5·7 vs. 16·2 ± 5·3 mV, respectively (P = 0·014). Maximal response to amiloride was also higher in FHH compared with controls: 14·8 ± 3·5 vs. 10·0 ± 4·8 mV, respectively (P = 0·03). In CF these values were 42·9 ± 9·3 and 29·9 ± 7·4 mV, respectively. The kinetics of the amiloride effect were faster in FHH, and as first reported here also in CF, compared with controls. At 30 s, amiloride‐inhibitable residual PD in FHH was 50 ± 30 vs. 81 ± 9% in controls (P = 0·0003) and 56 ± 7% in CF. The response to chloride‐free and isoproterenol solutions, which determines chloride transport activity, was similar in FHH compared with controls [16·0 ± 8·6 vs. 10·4 ± 5·9 mV (P = 0·08)]. Sweat conductivity in FHH was 49·7 ± 7·3 vs. 38·2 ± 8·1 mmol (NaCl eq) L^?1 in 16 controls (P = 0·007) and 94·0 ± 19·3 in CF. Conclusions Mutant WNK4 increases Na⁺ transport in airways, and therefore it is regulated by wild‐type WNK4. This may be caused by a regulation of ENaC or a K⁺ channel.     

Neurophysiological correlates of eye movement desensitization and reprocessing sessions: preliminary evidence for traumatic memories integration

We have investigated the potential role of eye movement desensitization and reprocessing (EMDR) in enhancing the integration of traumatic memories by measuring EEG coherence, power spectra and autonomic variables before (pre‐EMDR) and after (post‐EMDR) EMDR sessions during the recall of patient's traumatic memory. Thirteen EMDR sessions of six patients with post‐traumatic stress disorder were recorded. EEG analyses were conducted by means of the standardized Low Resolution Electric Tomography (sLORETA) software. Power spectra, EEG coherence and heart rate variability (HRV) were compared between pre‐ and post‐EMDR sessions. After EMDR, we observed a significant increase of alpha power in the left inferior temporal gyrus (T = 3·879; P = 0·041) and an increased EEG coherence in beta band between C3 and T5 electrodes (T = 6·358; P<0·001). Furthermore, a significant increase of HRV in the post‐EMDR sessions was also observed (pre‐EMDR: 6·38 ± 6·83; post‐EMDR: 2·46 ± 2·95; U‐Test= 45, P = 0·043). Finally, the values of lagged coherence were negatively associated with subjective units of disturbance (r(24) = ?0·44, P<0·05) and positively associated with parasympathetic activity (r(24)=0·40, P<0·05). Our results suggest that EMDR leads to an integration of dissociated aspects of traumatic memories and, consequently, a decrease of hyperarousal symptoms [Correction made here after initial publication].     

High-density lipoprotein cholesterol, C-reactive protein, and prevalence and severity of coronary artery disease in 5641 consecutive patients undergoing coronary angiography

Background Although high‐density lipoprotein cholesterol (HDL‐C) and C‐reactive protein (CRP) are well‐established predictors for future cardiovascular events, little information is available regarding their correlation with the prevalence and severity of angiographically evaluated coronary artery disease (CAD). Material and methods Five thousand six hundred forty‐one consecutive patients undergoing coronary angiography for the evaluation of CAD were analysed. Cardiovascular risk factors were assessed by routine blood chemistry and questionnaire. CAD severity was graded by visual estimation of lumen diameter stenosis with significant stenoses defined as lumen diameter reduction of ≥ 70%. Coronary angiograms were graded as one‐, two‐ or three‐vessel disease, as nonsignificant CAD (lumen irregularities < 70%) or non‐CAD. Results HDL‐C (60·3 ± 18·5 vs. 51·9 ± 15·3 mg dL^?1; P < 0·001) was higher and CRP was lower (0·65 ± 1·68 vs. 1·02 ± 2·38 mg dL^?1; P < 0·001) in non‐CAD (n = 1517) compared to overall CAD patients (n = 4124). CAD patients were older (65·2 ± 10·5 years vs. 59·9 ± 11·4 years), more often diabetics (19·2% vs. 10·6%) and hypertensives (79·2% vs. 66·0%) and included more smokers (18·8% vs. 16·5%) (all P < 0·005). Low‐density lipoprotein cholesterol (124·5 ± 38·3 vs. 126·0 ± 36·3 mg dL^?1; P = NS) was similar in overall CAD and non‐CAD patients with more statin users (43·4% vs. 27·9%; P < 0·001) among CAD patients. Comparing non‐CAD with different CAD severities using analysis of variance, results did not change substantially. In a multivariate analysis, HDL‐C and CRP remained independently associated with the prevalence of CAD. In addition, HDL‐C is also a potent predictor for the severity of CAD. Conclusions In this large consecutive patient cohort, HDL‐C and CRP are independently associated with the prevalence of CAD. In this analysis, HDL‐C is an even stronger predictor for CAD than some other major classical risk factors.     

Improvement of glycaemic control by nateglinide decreases systolic blood pressure in drug-naive patients with type 2 diabetes

Background It has been speculated that oral hypoglycaemic agents that block K‐ATP channels could potentially increase blood pressure by blocking such channels in vascular myocytes. No information about this issue exists regarding nateglinide. Design A multicentre, double‐blind, placebo‐controlled, randomized trial was conducted in 109 drug‐naive 30‐ to 75‐year‐old patients with type 2 diabetes and < 5 years of diabetes diagnosis, who are not taking antihypertensive drugs. These patients were assigned to receive placebo or fixed doses of nateglinide (120 mg before each main meal: breakfast, lunch and dinner) and evaluated at weeks 0 and 12 for (i) body mass index and blood pressure; (ii) standard laboratory tests, including haemoglobin A1c (HbA1c) and fasting plasma glucose; and (iii) incremental area under the curve for glucose and C‐peptide after a standardized liquid breakfast challenge, homeostasis model assessment (HOMA)‐B% (as surrogate of β‐cell activity) and HOMA‐S% (as surrogate of insulin sensitivity). Results At the end of the follow‐up period, patients in the nateglinide group (n = 55), compared to patients in the placebo group (n = 54), showed lower values of HbA1c (6·7 ± 0·6 vs. 7·2 ± 0·7%, respectively; P < 0·001), fasting plasma glucose (7·9 ± 2·1 vs. 8·5 ± 2·0 mmol L^?1; P = 0·023) and systolic blood pressure (125·3 ± 15·4 vs. 129·3 ± 18·7 mmHg; P = 0·015), and higher values of HOMA‐B%[75·7 (51·8–99·4) vs. 57·7 (42·2–83·4); P = 0·033]. A positive correlation was found between changes in HbA1c and systolic blood pressure in the nateglinide group (r = 0·355, P = 0·011). Conclusions In drug‐naive patients with type 2 diabetes, the improvement in glycaemic control with nateglinide is associated with a decrease in systolic blood pressure.     

Effects of short‐term detraining following blood flow restricted low‐intensity training on muscle size and strength

We investigated the effects of 3 weeks of detraining on muscle cross‐sectional area (CSA) and one‐repetition maximum strength (1‐RM) in young men who had previously participated in 6 weeks (3 days week^?1) of bench press training [blood flow restricted low‐intensity (LI‐BFR; n = 10, 20% 1‐RM) or high‐intensity (HI; n = 7, 75% 1‐RM)]. Bench press 1‐RM and muscle CSA of triceps brachii (TB) and pectoralis major (PM) were evaluated before (pre) and after training period (post) as well as after detraining period (detraining). Bench press 1‐RM was higher at both post and detraining than at pre for LI‐BFR (P<0·01) and the HI (P<0·01). TB and PM muscle CSA were higher at both post and detraining than at pre for the HI group (P<0·01), while the LI‐BFR group only increased (P<0·01) at post. Relative dynamic strength (1‐RM divided by TB muscle CSA) was higher at both post and detraining than at pre for the HI group (P<0·01), while the LI‐BFR group only increased (P<0·01) at detraining. In conclusion, increased muscle strength following 6 weeks of training with LI‐BFR as well as HI was well preserved at 3 weeks of detraining. HI‐induced muscle strength appears to be dependent upon both neural adaptations and muscle hypertrophy with training and detraining. On the other hand, LI‐BFR‐induced muscle strength appears to be related primarily to muscle hypertrophy with training and to neural adaptations with detraining.     

Is arterial stiffening in Alström syndrome linked to the development of cardiomyopathy?

Background Alström syndrome (AS) is a rare autosomal recessive condition characterized by retinal degeneration, childhood obesity, and severe insulin resistance. Dilated cardiomyopathy of unknown aetiology is a well‐recognized and potentially lethal complication. The aim of this study was to investigate the relationship between vascular function, hyperinsulinaemia and cardiac performance in AS. Materials and methods Fifteen subjects with AS (mean age 21 years, range 10–35) were studied and compared with age‐, sex‐, and blood pressure‐matched healthy controls. Large artery stiffness and wave reflections were assessed in both groups by measuring aortic and brachial pulse wave velocity (PWV) (carotid‐femoral and carotid‐radial) and augmentation index (AIX) (Sphygmocor). In AS subjects, left ventricular function was assessed by echocardiography and metabolic parameters including fasting insulin, glucose, lipids and brain natriuretic peptide were also measured. Results Comparing AS subjects vs. controls (mean ± SD), AIX was elevated in AS subjects (18 ± 9% vs. 3 ± 11%, P < 0·0001). No significant changes in brachial PWV (8·1 ± 1·3 m s⁻¹ vs. 7·3 ± 1·1 m s⁻¹, P = 0·14) or aortic PWV (6·5 ± 1·1 m s⁻¹ vs. 6·0 ± 1·0 m s⁻¹, P = 0·26) were observed. AS subjects were hyperinsulinaemic and had disturbances in lipid profiles relative to controls. No correlations were observed between vascular, metabolic and echocardiographic parameters. Conclusions In AS there are alterations in the shape of the central arterial pressure waveform associated with augmented aortic systolic pressure and indicative of increased wave reflection. Unfavourable central arterial haemodynamics in AS may contribute to the development of cardiomyopathy but other aetiological factors are probably involved.     

Metabolic and anti-inflammatory benefits of eccentric endurance exercise - a pilot study

Background Eccentric endurance exercise (e.g. hiking downwards) is less strenuous than concentric exercise (e.g. hiking upwards) but its potential to reduce cardiovascular risk is unknown. Materials and methods We randomly allocated 45 healthy sedentary individuals (16 men and 29 women, mean age 48 years) to one of two groups, one beginning with two months of hiking upwards, the other with two months of hiking downwards the same route, with a crossover for a further two months. For the opposite way, a cable car was used where compliance was recorded electronically. The difference in altitude was 540 metres; the distance was covered three to five times a week. Fasting and postprandial metabolic profiles were obtained at baseline and after the two month periods of eccentric and concentric exercise, respectively. Results Forty‐two of the 45 participants completed the study; the compliance rate was therefore 93%. Compared with baseline, eccentric exercise lowered total cholesterol (by 4·1%; P = 0·026), low‐density lipoprotein (LDL) cholesterol (by 8·4%, P = 0·001), Apolipoprotein B/Apolipoprotein A1 ratio (by 10·9%, P < 0·001), homeostasis model assessment of insulin resistance scores (by 26·2%, P = 0·017) and C‐reactive protein (by 30·0%; P = 0·007); the magnitude of these changes was comparable to that of concentric exercise. Eccentric exercise improved glucose tolerance (by 6·2%, P = 0·023), whereas concentric exercise improved triglyceride tolerance (by 14·9%, P = 0·022). Conclusions Eccentric endurance exercise is a promising new exercise modality with favourable metabolic and anti‐inflammatory effects and is well applicable to sedentary individuals.     

Glucagon-like peptide-1 reduces the pulsatile component of testosterone secretion in healthy males

Background Glucagon‐like‐peptide‐1 (7–36) amide (GLP‐1), a potent regulator of glucose homeostasis, has been implicated in the control of hypothalamic‐pituitary function. In vivo it is a relevant neuroendocrine modulator of gonadotropin‐releasing hormone release, suggesting its possible role as a metabolic signal to the reproductive system. The present study was undertaken to establish its effect on luteinizing hormone (LH) and testosterone secretion in nine healthy male volunteers. Materials and methods Each subject underwent an oral glucose tolerance test to establish LH, testosterone, and GLP‐1 responses to glucose. Euglycaemic clamp experiments (6 h) were performed on two occasions with saline or with a constant infusion of GLP‐1 (0·4 pmol kg^?1 min ^?1). Blood samples were drawn at 10‐min intervals to measure the pulsatile pattern of LH and testosterone secretion. Results Ingestion of oral glucose resulted in a reduction in plasma testosterone levels at 30 min compared with baseline (P < 0·004) despite unaltered LH levels (P = 0·5). Constant GLP‐1 infusion resulted in no change in LH (P = 0·83), testosterone (P = 0·96), follicle stimulating hormone (FSH) (P = 0·86) and leptin levels (P = 0·3). Pulse analysis revealed no significant difference in the number (P = 0·1) or median absolute amplitude (P = 0·3) of the LH pulses. However, there was a significant decrease in the number (3·0 ± 0·6 vs. 1·3 ± 0·4; P < 0·05) and a tendency for increased duration of testosterone pulses (97·4  16·7 vs. 170  27·1 min; P = 0·06). Conclusion Oral glucose ingestion and intravenous GLP‐1 infusion reduce the pulsatile component of testosterone secretion by a mechanism independent of LH release.     

Relationship between peak cardiac pumping capability and indices of cardio-respiratory fitness in healthy individuals

Cardiac power output (CPO) is a unique and direct measure of overall cardiac function (i.e. cardiac pumping capability) that integrates both flow‐ and pressure‐generating capacities of the heart. The present study assessed the relationship between peak exercise CPO and selected indices of cardio‐respiratory fitness. Thirty‐seven healthy adults (23 men and 14 women) performed an incremental exercise test to volitional fatigue using the Bruce protocol with gas exchange and ventilatory measurements. Following a 40‐min recovery, the subjects performed a constant maximum workload exercise test at or above 95% of maximal oxygen consumption. Cardiac output was measured using the exponential CO₂ rebreathing method. The CPO, expressed in W, was calculated as the product of the mean arterial blood pressure and cardiac output. At peak exercise, CPO was well correlated with cardiac output (r = 0·92, P<0·01), stroke volume (r = 0·90, P<0·01) and peak oxygen consumption (r = 0·77, P<0·01). The coefficient of correlation was moderate between CPO and anaerobic threshold (r = 0·47, P<0·01), oxygen pulse (r = 0·57, P<0·01), minute ventilation (r = 0·53, P<0·01) and carbon dioxide production (r = 0·56, P<0·01). Small but significant relationship was found between peak CPO and peak heart rate (r = 0·23, P<0·05). These findings suggest that only peak cardiac output and stroke volume truly reflect CPO. Other indices of cardio‐respiratory fitness such as oxygen consumption, anaerobic threshold, oxygen pulse, minute ventilation, carbon dioxide production and heart rate should not be used as surrogates for overall cardiac function and pumping capability of the heart.     

Dynamic cerebral autoregulation to induced blood pressure changes in human experimental and clinical sepsis

Previous studies have demonstrated that dynamic cerebral autoregulation to spontaneous fluctuations in blood pressure is enhanced following lipopolysaccharide (LPS) infusion, a human experimental model of early sepsis, whereas by contrast it is impaired in patients with severe sepsis or septic shock. In this study, we hypothesized that this pattern of response would be identical during induced changes in blood pressure. Dynamic cerebral autoregulation was assessed in nine healthy volunteers and six septic patients. The healthy volunteers underwent a 4‐h intravenous infusion of LPS (total dose: 2 ng kg^?1). Mean arterial blood pressure (MAP, arterial transducer) and middle cerebral artery blood flow velocity (MCAv, transcranial Doppler ultrasound) were recorded continuously during thigh‐cuff deflation‐induced changes in MAP for the determination of a modified rate of regulation (RoR). This was performed before and after LPS infusion in healthy volunteers, and within 72 h following clinical diagnosis of sepsis in patients. In healthy volunteers, thigh‐cuff deflation caused a MAP reduction of 16 (13–20) % at baseline and 18 (16–20) % after LPS, while the MAP reduction was 12 (11–13) % in patients (P<0·05 versus volunteers at baseline; P<0·01 versus volunteers after LPS). The corresponding RoR values increased from 0·46 (0·31–0·49) s^?1 at baseline to 0·58 (0·36–0·74) s^?1 after LPS (P<0·05) in healthy volunteers, whereas they were similar to values observed in patients [0·43 (0·36–0·52) s^?1; P = 0·91 versus baseline; P = 0·14 versus LPS]. While our findings support the concept that dynamic cerebral autoregulation is enhanced during the very early stages of sepsis, they remain inconclusive with regard to more advanced stages of disease, because thigh‐cuff deflation failed to induce sufficient MAP reductions in patients.     

Quantification of Bax and Bcl2 in polymorphonuclear leukocytes from haemodialysis patients: relation to hydrogen peroxide

Background Bax and Bcl2 are two apoptosis‐related molecules that play an important role in determining cell fate following oxidative injury. In the present study, we explored the relation of hydrogen peroxide (H₂O₂) generation by polymorphonuclear cells (PMNs) to the cytosolic expression of Bax and Bcl2 proteins and apoptosis in haemodialysis (HD) patients. Methods Cytosolic generation of H₂O₂ by PMNs from control subjects and HD patients was measured by flow cytometry using the dichlorofluorescin diacetate assay. Bax and Bcl2 expression was detected by flow cytometry using FITC‐conjugated antibodies. Apoptosis was quantified by flow cytometry using propidium iodide nuclear staining. To examine the effect of H₂O₂ on Bcl2 and Bax expression, PMNs from control subjects were briefly exposed to H₂O₂ (0·1–100 µM) for 10 min and then washed and cultured for 6 h, with or without catalase, a H₂O₂ detoxifying molecule. Bcl2 and Bax expression was determined by Western blot analysis. Results Basal H₂O₂ generation by resting PMNs was significantly higher in HD patients compared with control subjects (211 ± 115 vs. 23 ± 5 MFI; P = 0·002). However, PMNs from HD patients did not undergo accelerated programmed cell death compared with control subjects (58 ± 7% vs. 46 ± 5; P = 0·14). Polymorphonuclear cells cytosolic Bcl2 was undetected in control subjects but detected in 25% of HD patients, and Bax was more frequently detected in PMNs from HD patients (75% vs. 67%; P = 0·04). In the HD patients with detectable cytosolic Bax and Bcl2 proteins, the Bax to Bcl2 ratio inversely correlated with H₂O₂ levels (P < 0·0001). Finally, brief exposure of PMNs to 0·1–100 µM of H₂O₂ resulted in a marked increase in Bcl2 expression (P = 0·001), which was prevented by catalase (P = 0·05). There was no apparent effect on Bax expression. Conclusions This study demonstrates that in HD patients, high‐resting cytosolic H₂O₂ production by PMNs is not associated with accelerated in vitro apoptosis, and that the Bax/Bcl2 system may counter‐balance the deleterious effects of reactive oxygen species in human PMNs.     

Lipoprotein (a) and acute-phase response in patients with vestibular neuronitis

Background Vestibular neuronitis (VN) is a relatively common condition characterized by the acute onset of vertigo, nausea and vomiting, in the absence of auditory or central nervous system involvement. The exact aetiology (inflammatory, viral or vascular?) remains obscure. Lipoprotein (a) [Lp(a)] is an atherogenic particle. Its serum levels are mainly genetically determined and vary widely between individuals. Whether Lp(a) is consistently a positive acute‐phase reactant is controversial. Purpose We evaluated the alterations in lipidaemic parameters and serum biological markers (including acute‐phase reactants) in adult patients presenting acutely with VN. Subjects and methods A total of 34 consecutive VN patients (24 men and 11 women) and 37 apparently healthy controls (25 men and 12 women) were studied. Laboratory evaluation was performed during the acute episode and 6 months later (stable state). Results Serum Lp(a) concentrations were significantly lower at the time of presentation (median value 6·4 vs. 16·4 mg dL^?1 in the stable state, P < 0·001), whereas fibrinogen levels were significantly higher during the acute episode than in the stable state (median value 293·0 vs. 202·0 mg dL^?1, respectively, P < 0·0001). During the acute episode, plasma fibrinogen correlated with CRP levels (Spearman r = 0·84, P < 0·0001). By contrast, inverse correlations were noted between Lp(a) levels and CRP (Spearman r = ?0·47, P = 0·007) as well as between Lp(a) and fibrinogen levels (Spearman r = ?0·35, P = 0·05). Conclusion Vestibular neuronitis episodes are associated with evidence of an acute inflammatory response as reflected by significant elevations in plasma fibrinogen and CRP concentrations, whereas Lp(a) behaves as a negative acute‐phase reactant.     

Measurement of maximal isometric torque and muscle quality of the knee extensors and flexors in healthy 50‐ to 70‐year‐old women

Muscle quality is defined as strength per unit muscle mass. The aim of this study was to measure the maximal voluntary isometric torque of the knee extensor and flexor muscle groups in healthy older women and to develop an index of muscle quality based on the combined knee extensor and flexor torque per unit lean tissue mass (LTM) of the upper leg. One hundred and thirty‐six healthy 50‐ to 70‐year‐old women completed an initial measurement of isometric peak torque of the knee extensors and flexors (Con‐Trex MJ; CMV AG, Dubendorf, Switzerland) that was repeated 7 days later. Subsequently, 131 women returned for whole‐ and regional‐body composition analysis (iDXA^?; GE Healthcare, Chalfont St Giles, Buckinghamshire, UK). Isometric peak torque demonstrated excellent within‐assessment reliability for both the knee extensors and flexors (ICC range: 0·991–1·000). Test–retest reliability was lower (ICC range: 0·777–0·828) with an observed mean increase of 5% in peak torque [6·2 (17·2) N m] on the second day of assessment (P<0·001). The relative mean decrease in combined isometric peak torque (?12·2%; P = 0·001) was double that of the relative, non‐significant, median difference in upper leg LTM (?5·3%; P = 0·102) between those in the 5th and 6th decade. The majority of difference in peak isometric torque came from the knee extensors (15·1 N m, P<0·001 versus 2·4 N m, P = 0·234). Isometric peak torque normalized for upper leg LTM (muscle quality) was 8% lower between decades (P = 0·029). These findings suggest strength per unit tissue may provide a better indication of age‐related differences in muscle quality prior to change in LTM.     

Functional near‐infrared spectroscopy to probe sensorimotor region activation during electrical stimulation‐evoked movement

This study used non‐invasive functional near‐infrared spectroscopy (fNIRS) neuroimaging to monitor bilateral sensorimotor region activation during unilateral voluntary (VOL) and neuromuscular electrical stimulation (NMES)‐evoked movements. Methods. In eight healthy male volunteers, fNIRS was used to measure relative changes in oxyhaemoglobin (O₂Hb) and deoxyhaemoglobin (HHb) concentrations from a cortical sensorimotor region of interest in the left (LH) and right (RH) hemispheres during NMES‐evoked and VOL wrist extension movements of the right arm. Results. NMES‐evoked movements induced significantly greater activation (increase in O₂Hb and concomitant decrease in HHb) in the contralateral LH than in the ipsilateral RH (O₂Hb: 0·44 ± 0·16 μM and 0·25 ± 0·22 μM, P = 0·017; HHb: ?0·19 ± 0·10 μM and ?0·12 ± 0·09 μM, P = 0·036, respectively) as did VOL movements (0·51 ± 0·24 μΜ and 0·34 ± 0·21 μM, P = 0·031; HHb: ?0·18 ± 0·07 μΜ and ?0·12 ± 0·04 μΜ, P = 0·05, respectively). There was no significant difference between conditions for O₂Hb (P = 0·144) and HHb (P = 0·958). Conclusion. fNIRS neuroimaging enables quantification of bilateral sensorimotor regional activation profiles during voluntary and NMES‐evoked wrist extension movements.     

Elevated VEGF-plasma levels in young patients with mild essential hypertension

Background Growing evidence shows that inflammation plays a pivotal role in the pathophysiology of essential hypertension (EH). Vascular endothelial cell growth factor (VEGF) is currently discussed as a possible mediator of inflammation. To investigate the hypothesis that VEGF plays a role as an inflammatory mediator in EH we performed the present pilot study of young patients in a very early stage of EH. Materials and methods 15 young patients with mild EH [33·8 ± 7·3 years, systolic blood pressure (SBP): 143·8 ± 10·5 mmHg, diastolic blood pressure (DBP): 88·2 ± 11·1 mmHg, mean arterial pressure (MAP) 106·6 ± 10·4 mmHg] and 15 healthy controls (31·7 ± 10·6 years) were examined. Blood was drawn from a peripheral vein and serum levels of VEGF, monocyte‐chemoattractant‐protein (MCP)‐1, high‐sensitivity C‐reactive protein (hsCRP), interleukin (IL)‐6, and tumour‐necrosis‐factor (TNF)‐α were measured via commercially available enzyme‐linked immunoassays. Results Hypertensives showed increased plasma levels of VEGF (P < 0·05) and MCP‐1 (P < 0·05). VEGF positively correlated with MAP (r = 0·46, P < 0·05) and MCP‐1 (r = 0·63, P < 0·01). Multivariate analysis demonstrated VEGF to be an independent predictor of MCP‐1 levels. Furthermore, hypertensives had higher levels of hsCRP (P < 0·01), IL‐6 (P < 0·001) and TNF‐α (P < 0·05). IL‐6 levels correlated with SBP (r = 0·59, P < 0·001), DBP (r = 0·67, P < 0·001) and MAP (r = 0·46, P < 0·001). A significant positive correlation was also found between hsCRP levels and SBP (r = 0·39, P < 0·05). Conclusions This pilot study demonstrates that in an early state of EH, inflammatory pathways have already been activated. Besides classical pro‐inflammatory cytokines, VEGF serum levels are significantly elevated. The positive correlation of VEGF with MCP‐1 is suggestive for the already described induction of MCP‐1 via VEGF.     

Evaluation of impaired dynamic cerebral autoregulation by the Mueller manoeuvre

Arterial blood pressure (ABP) shows polyphasic changes during the Mueller manoeuvre (voluntary negative intrathoracic pressure). The aim of the present study was to investigate (1) whether these changes could be applied to detect impaired dynamic cerebral autoregulation (dCA) in carotid stenosis and (2) whether the degree of indicated impairment correlates with transfer function phase as another current measure for dCA (deep breathing method) and CO₂‐reactivity. We examined 13 patients with severe unilateral carotid artery stenosis and 16 age‐matched controls during 15‐s Mueller manoeuvres (MM) at ?30 mmHg using bilateral transcranial Doppler sonography and non‐invasive ABP recordings (Finapres, 2300, Ohmeda, Englewood, CO, USA). After an initial biphasic oscillation, cerebral blood flow velocity (CBFV) and ABP decreased to below baseline. CBFV reincreased in controls and on contralateral sides in patients 6·0 s (3·8–9·5 s, median and range) after the onset of the decrease, despite a further fall in ABP. CBFV over the affected side revealed a significantly delayed reincrease (8·0 (5·6–10·3) s; P<0·01) combined with a relatively flat and inertial amplitude behaviour. An applied autoregulation index derived from the MM (mROR), phase shift and CO₂‐reactivity were severely reduced on the affected side in patients (P<0·01). Reduction of the mROR correlated significantly with reduction of phase shift (r=0·69; P=0·002) and CO₂‐reactivity (r=0·78; P=0·002). In conclusion, the different cerebral haemodynamic pattern during the MM in patients is likely to reflect impaired dCA. The degree of indicated impairment correlates with that of transfer function phase and CO₂‐reactivity. Therefore, the MM represents a convenient method for grading of compromised cerebral haemodynamics in patients with carotid artery stenosis.     

Effect of set configuration on hemodynamics and cardiac autonomic modulation after high‐intensity squat exercise

The aim of this study was to compare the effect of two different high‐intensity resistance exercise (RE) set configurations on the following: systolic blood pressure (SBP), rate pressure product (RPP), heart rate (HR) variability (HRV), and HR complexity (HRC). Ten well‐trained males performed three parallel squat sets until failure (traditional training; TT) with the four repetitions maximum load (4RM), and a rest of 3 min between sets. Thereafter, participants performed a cluster training session (CT) of equated load but with resting time distributed between each repetition. Dependent variables were recorded before, during, and after RE. Mean SBP (25·7 versus 10·9% percentage increase; P = 0·016) and RPP (112·5 versus 69·9%; P = 0·01) were significantly higher in TT. The decrease in HRV after exercise and the drop of HRC during exercise were similar in CT and TT. Change of standard deviation of normal RR intervals after TT correlated with change in SBP (r = 0·803; P = 0·009) while the change of Sample Entropy during exercise correlated with the increment of RPP during CT (ρ = ?0·667; P = 0·05). This study suggests that set configuration influences acute cardiovascular responses during RE. When intensity, volume and work‐to‐rest ratio are equated, CT is less demanding in terms of SBP and RPP. A greater hemodynamic response during exercise would be associated with a faster parasympathetic recovery.     

Lipid peroxidation and mucin secretagogue activity in bile of gallstone patients

Background Chronic inflammation of the gallbladder wall and mucin hypersecretion are considered to be important factors in the pathogenesis of cholesterol gallstone disease. The aim of the study was to compare mucin concentration and mucin secretagogue activity with lipid peroxidation in gallbladder bile of patients with cholesterol or pigment stones. Material and methods We studied mucin concentration and, as a marker of lipid peroxidation, malondialdehyde concentration in 11 rapid (1 to 3 days) and eight non‐nucleating (> 21 days) gallbladder biles of patients with cholesterol or pigment stones. Furthermore, the mucin secretagogue activity of rapid and non‐nucleating gallbladder biles, as well as 1–5 µmol L⁻¹ malondialdehyde on cultured gallbladder epithelial cells, was determined. Results Our data show an increased malondialdehyde (7·2 ± 1·8 vs. 3·8 ± 0·5 µmol L⁻¹, P = 0·01) and mucin concentration (0·9 ± 0·09 vs. 0·41 ± 0·03 mg mL⁻¹, P = 0·01) and an increased mucin secretagogue activity (2·0 ± 0·5 vs. 1·1 ± 0·3 mucin secretion/control, P = 0·04) and cholesterol saturation index (1·2 ± 0·1 vs. 08 ± 0·1, P = 0·04) in rapid as compared to non‐nucleating gallbladder biles. Malondialdehyde stimulated mucin secretion of cultured gallbladder epithelial cells in a concentration dependent manner. Conclusions Our results support a promoting effect of gallbladder mucin hypersecretion by lipid peroxidation leading to rapid formation of cholesterol crystals in gallbladder bile. These findings suggest that besides hypersecretion of cholesterol in bile, chronic inflammation of the gallbladder wall is implicated in the pathogenesis of cholesterol gallstone disease.