Disparate effects of adalimumab and fumaric acid esters on cardiovascular risk factors in psoriasis patients: results from a prospective, randomized, observer-blinded head-to-head trial.

BACKGROUND: The effect of adalimumab and fumaric acid esters (FAE) on the cardiovascular risk associated with psoriasis has only been investigated scarcely in randomized controlled studies. OBJECTIVE: The aim of this prospective, randomized controlled head-to-head trial was to compare the influence of adalimumab and FAE on cardiovascular disease markers in psoriasis patients. METHODS: Sixty-five patients with moderate to severe plaque psoriasis were randomly assigned to adalimumab or FAE treatment for 6 months. Cardiovascular haemodynamic parameters [flow-mediated dilation (FMD), nitro-glycerine mediated dilation (NMD) and carotid intima-media thickness (CIMT), blood pressure] were assessed at baseline (v0) and after 6 months (v6). Cutaneous disease severity, inflammatory and lipid cardiovascular risk markers were analysed at baseline(v0), after 3 (v3) and 6 months (v6). RESULTS: After 6 months of treatment FMD in the adalimumab group increased significantly [v0 5.9% (6.4% SD), v6 8.0% (4.8% SD), P = 0.048) but not in the FAE group. (v0 7.0% (4.1% SD), v6 8.4% (6.1% SD), P = 0.753]. This was paralleled by a significant decrease of high sensitive C-reactive protein (hsCRP) in the adalimumab group in comparison to the FAE group (v0: 0.39 mg/dL (0.38 SD), v6: 0.39 mg/dL (0.48 SD), P = 0.043). No significant changes were observed in any other haemodynamic parameters. FAE, however, additionally decreased total cholesterol (P = 0.046) and apolipoprotein B (P = 0.041) levels compared to adalimumab. Mean Psoriasis Area and Severity Index (psoriasis area severity score) reduction was greater but not significant (P = 0.116) under adalimumab treatment compared to FAE treatment [-71.1% (29.9 SD) vs. -54.6% (45.7%)]. CONCLUSION: In our study, both treatments were documented to exert effects on the cardiovascular system. While adalimumab showed anti-inflammatory effects and improved FMD, FAE interacted favourably with the cholesterol metabolism.

Impact of exercise on bone mineral density, fall prevention, and vertebral fragility fractures in postmenopausal osteoporotic women.

Osteoporosis is the most prevalent bone disease worldwide and predisposes affected individuals to fragility fractures. Exercise has been shown to have multiple health benefits in post-menopausal osteoporotic women, but often recommendations regarding the benefits of specific exercise types are vague. Improving bone mineral density (BMD) is an essential component in any program to prevent osteoporotic vertebral fractures. The objective of this report is to briefly review the current understanding on the impact of exercise on BMD in postmenopausal women as it pertains to fragility fractures. Broad categories of exercises include aerobic, resistance, stretching, and balance. Tai Chi, Yoga, and Pilates are a heterogeneous group of specific exercise modalities that can span multiple categories. Current literature suggests that only resistance type exercises have a convincing impact on BMD. Core-strengthening exercises and attention to posture/balance can help mitigate falls. A number of barriers affect patient compliance and accessibility to exercise. In summary, exercise should be included in any multi-modality osteoporosis treatment plan with the goal of sustained exercise throughout life. If possible, osteoporotic women should be on a resistance-based regimen incorporating weight-bearing exercises, and also target posture and balance. Healthcare providers and educators should have resources readily available for patients.

Evidence of carotid atherosclerosis in orthopantomograms and the risk for future cardiovascular events.

BACKGROUND: Evidence of carotid atherosclerosis can be detected in 3 to 5% of orthopantomogram (OPG) investigations. The clinical impact of these findings is unknown. We investigated the association of OPG findings of carotid atherosclerosis with the occurrence of future cardiovascular adverse events. PATIENTS AND METHODS: We randomly selected 411 of 1268 participants with pre-existent cardiovascular disease from the prospective Inflammation in Carotid Arteries Risk for Arthrosclerosis Study (ICARAS) and assessed their OPGs for the presence of calcified atherosclerotic lesions or indirect signs of atherosclerosis, such as surgical clips or intravascular stents. The degree of carotid stenosis was measured by duplex ultrasound investigations. Patients were then followed for median 39 months (interquartile range 33 to 44 months) for the occurrence of major adverse cardiovascular events (MACE) including myocardial infarction, coronary revascularisation, stroke and death. RESULTS: We found no statistically significant association between the presence of carotid atherosclerosis detected on OPGs and the presence of a significant carotid stenosis (left carotid artery kappa=0.08; right carotid artery kappa=0.12), or the degree of carotid stenosis (P=0.20). Furthermore, the presence of OPG signs of carotid atherosclerosis was not statistically significant associated with future MACE (adjusted hazard ratio 0.92, 95% confidence interval 0.59 to 1.42; P=0.70). CONCLUSIONS: Evidence of carotid plaque revealed by OPGs in patients with previously known cardiovascular disease is no useful prognostic marker for MACE. Detection of carotid atherosclerosis by OPGs in these patients therefore has no clinical consequence.

Frequency-specific threshold determination with the CERAgram method: basic principle and retrospective evaluation of data.

A method for the objective evaluation of the hearing threshold using cortical evoked response audiometry was developed. The method results in a kind of objective audiogram, visualizing the significance of an auditory evoked potential (AEP) in a scheme similar to a conventional audiogram. In the present implementation of the method, four frequencies are tested quasi-simultaneously (500, 1000, 2000 and 3000 Hz; intensity steps of 5 dB). The significance of an evoked potential is assessed by means of the Rayleigh test, which is applied to the phase values derived from certain time windows of the single-trial epochs. A retrospective analysis of 1, 920 threshold estimations in 240 subjects suggested that the detection threshold (lowest stimulus intensity yielding a significant response) was, on the average, 7.5 dB above the electrophysiological threshold (intensity where the AEP amplitude vanishes). The grand-average amplitude-intensity characteristic was approximated by the function a(1 - exp(-I/b)), with a = 6.25 microV, b = 22.3 dB and I representing the intensity (in decibels) relative to the electrophysiological threshold.

Auditory afterimage: tonotopic representation in the auditory cortex.

The auditory afterimage is a sensation which occurs for several seconds after the exciting acoustic signal has been switched off, and which roughly corresponds to the inverse of the spectrum of the exciting signal. In contrast to the well-known visual afterimage, the physiological mechanism generating the auditory afterimage has been questionable so far. Neuromagnetic source imaging revealed that the source of cortical neural activity which coincides with the sensation of the afterimage is located in the auditory cortex and exhibits a tonotopic organization similar to that of the sustained response which occurs during continuous presentation of an acoustic stimulus. It is concluded that the neural processes leading to the generation of the two phenomena -sustained response and auditory afterimage - are similar.

Tinnitus and event-related activity of the auditory cortex.

A neuromagnetic study in tinnitus patients and normal-hearing controls was performed with a modified contingent negative variation (CNV) paradigm. While the warning stimulus S1 was a tone burst at an intensity well above threshold, the imperative stimulus S2 was presented at a near threshold intensity because, in the majority of cases, the perceived loudness of tinnitus is very close to the threshold for a pure tone of the same frequency. Subjects had to respond to S2 by pressing a button until its offset was detected. In this case, instead of the usual sudden cut-off of the CNV after the perception of S2, a slow negative deflection develops, the post-imperative negative variation (PINV). Its initial portion probably indicates the development of a second initial CNV because the subject had to attend also to the offset of S2. The neuromagnetic data were analysed both in the time domain and in the frequency domain (short-time spectral analysis of the classical EEG bands). The time domain waveform as well as the spectrotemporal patterns of the MEG bands exhibited deviations from the normal pattern in several tinnitus subgroups, depending on the characteristics of tinnitus (tonal vs. noisiform, monaural vs. binaural) and on the stimulation conditions (tinnitus side vs. non-tinnitus side).

Increased auditory cortical representation in musicians.

Acoustic stimuli are processed throughout the auditory projection pathway, including the neocortex, by neurons that are aggregated into 'tonotopic' maps according to their specific frequency tunings. Research on animals has shown that tonotopic representations are not statically fixed in the adult organism but can reorganize after damage to the cochlea or after training the intact subject to discriminate between auditory stimuli. Here we used functional magnetic source imaging (single dipole model) to measure cortical representations in highly skilled musicians. Dipole moments for piano tones, but not for pure tones of similar fundamental frequency (matched in loudness), were found to be enlarged by about 25% in musicians compared with control subjects who had never played an instrument. Enlargement was correlated with the age at which musicians began to practise and did not differ between musicians with absolute or relative pitch. These results, when interpreted with evidence for modified somatosensory representations of the fingering digits in skilled violinists, suggest that use-dependent functional reorganization extends across the sensory cortices to reflect the pattern of sensory input processed by the subject during development of musical skill.

Methohexital-induced changes in spectral power of neuromagnetic signals: beta augmentation is smaller over the hemisphere containing the epileptogenic focus.

Previous research has suggested that methohexital, a short-term barbiturate, alters activity in the primary epileptogenic area. It can be assumed that drug-induced activation of the epileptogenic focus provides a rapid and safe method to obtain a sufficient amount of information relevant for the lateralization and localisation of the primary epileptogenic area. This study shows that methohexital changes spectral power in the beta band derived from magnetoencephalographic (MEG) signals over the hemisphere ipsilateral to the primary epileptogenic area. This effect was demonstrated for 10/13 of the investigated patients suffering from unilateral temporal lobe epilepsy (TLE). The side and location of the primary epileptogenic area of these patients (5 left TLE, 8 right TEL) was determined invasively during presurgical evaluation. During a 1-2 minute interval after intravenous bolus injection of 100 mg methohexital a clear lateralization effect in the beta band was observed, which differed marginally between fronto-central, fronto-temporal and temporo-parietal brain regions. In addition, bilateral spectral power changes were obtained in the theta, alpha and gamma bands that differed between brain regions. Analyses of simultaneously recorded scalp electroencephalographic (EEG) data revealed effects consistent with those of the MEG analysis. The reduced enhancement of beta band spectral power of MEG recordings provides a potential application for the non-invasive lateralization of the primary epileptogenic area.

[Decrease in cardiovascular disease mortality in the Czech Republic from 1984 to 1993 and its possible causes]. / Pokles úmrtnosti na kardiovaskulární onemocnení v Ceské republice v období 1984-1993 a jeho mozné príciny.

BACKGROUND: The objective of the investigation was to evaluate the ten-year development of the cardiovascular mortality rate in two population groups in the age bracket from 25 to 64 years, i.e. in subjects living in six districts which participated in the international WHO project MONICA and in the population of the whole Czech Republic. METHODS AND RESULTS: Data on the mortality rate in 1984-1993 for the age group from 25-64 years were provided by the Institute of Health Information and Statistics, information on the prevalence of risk factors was obtained in three cross-sectional studies implemented in six districts as part of the MONICA project in 1985, 1988 and 1992. In the mortality rate per 100,000 population in the six districts the following changes were revealed (in parentheses the values for 1984 and 1993 are given): men - a statistically significant declining trend in the from all caused mortality (849.3-742.5; p < 0.001) and cardiovascular mortality (367.2-280.4; p < 0.001) and cerebrovascular mortality (69.7-44.8; p < 0.001). In the mortality from ischaemic heart disease (215.7-170.6; ns) a declining trend was not recorded. In women aged 25-64 years in the six districts there was a statistically significant decline of the mortality from all caused (359.5-322.1; p < 0.001), the cardiovascular mortality (115.6-100.6; p < 0.001) and cerebrovascular mortality (31.1-23.6; p < 0.001). The mortality from ischaemic heart disease did not change (49.2-48.8; ns). In the population of the Czech Republic in men the following were detected: a drop of the from all caused mortality (907.1-784.8; P < 0.001), the cardiovascular mortality (383.5-308.4; p < 0.001) and cerebrovascular mortality (76.5-55.3; p < 0.001). Also in women of the Czech Republic a decline of the mortality from all caused was recorded (390.1-328.5; p < 0.001), the cardiovascular mortality (135.3-103.8; p < 0.001), ischaemic heart disease (58.0-48.6; p < 0.001) and cerebrovascular mortality (43.5-27.4; p < 0.001). In 1990 an increased cardiovascular mortality was recorded in men different from the trend during 1984-1993, statistically significant in the Czech Republic (p < 0.05) and in the six districts (p < 0.05). The reasons of this trend are not clear. The role of health services in the mortality drop is not clear, although available data indicate their improvement. Favourable changes were found in risk factors: during the period from 1985-1992 the prevalence of hypercholesterolaemia declined significantly in men and women, the prevalence of hypertension in women and the prevalence of smoking in men declined in the six districts. From nationwide data ensues that after 1989 significant changes occurred in the diet of the Czech population. The meat consumption declined by 1993 by 13%, the milk and dairy product consumption by 26.8% the butter consumption by 43.6% the consumption of vegetable fats increased by 16%, of vegetables by 8%, tropical fruit by 43.2%. These changes probably had an impact on the cholesterol level and BMI of the Czech population. CONCLUSIONS: In the declining cardiovascular mortality trend during 1984-1993 the following may have participated: improved medical care, dietary changes, improvement of the risk profile and other, in particular socioeconomic factors. With regard to the close temporal association of the investigated changes it may be assumed that this development is at least partly associated with changes of the political and economic position in the Czech Republic after 1989.

Magnetic brain imaging of extinction processes in human classical conditioning.

By recording neuromagnetic events during aversive classical conditioning, we examined the extinction of a previously described conditioned response. Averaging over non-reinforced exposures to the conditioned stimulus revealed magnetic activity in the secondary somatosensory and insular cortices, appearing between 110 and 140 ms after the omitted unconditioned electric shock. We suggest this activity to be elicited by the discrepancy between shock expectancy and perceptual processes associated with the omission of the unconditioned stimulus, reflecting one of several brain processes in extinction.

Possibilities and limitations of magnetic source imaging of methohexital-induced epileptiform patterns in temporal lobe epilepsy patients.

The usefulness of MEG-based techniques in lateralizing and localizing the epileptogenic area was investigated in the present study. Spontaneous and methohexital-induced spikes were studied in a group of 15 patients with temporomesial epilepsy using a 37-channel neuromagnetometer. The accuracy of the magnetic source imaging was compared to the results of electrocorticographic (ECoG) recordings. Differences of drug-induced spike densities in the MEG recordings between both sides confirmed a similar lateralizing power of the MEG and ECoG recordings. Source location analyses based on a moving dipole model resp. a rotating dipole model were performed using a spherical head model. After subdivision of the volume of each patient's head, 8 cm3 cubicles containing at least 3 source locations were projected onto the individual MRI scan and resulted in source locations within or close to the presurgically defined primary epileptogenic area only in 3 of the 15 patients. Spike induction by methohexital has the advantage of shortening the recording period as compared to recordings of interictal epileptiform discharges. However, the correlation analyses of spike densities from MEG and ECoG recordings and the source location analyses from MEG recordings indicate that spike generated in deep temporomesial structures may escape the MEG registration.

Mismatch field to tone pairs: neuromagnetic evidence for temporal integration at the sensory level.

The mismatch field (MMF) to minor pitch changes in two experimental conditions was studied. Standard tones of 1000 Hz and deviant tones of 1050 Hz both of 50 ms duration were delivered in single tone condition. Paired tones of the same duration were used in the paired tone condition. The standard tone pair consisted of two 1000 Hz tones, whereas the deviant tone pair was composed of a 1000 Hz tone in the first position and a 1050 Hz tone in the second position with a silent interval of 15 ms between the two. Standards of 90% and deviants of 10% probability were presented in random order and with a randomized interstimulus interval between 600 and 900 ms. The source analysis showed a more lateral location for the MMF obtained in the paired tone condition (MMF.P) compared to the MMF elicited by the single deviants (MMF.S). The source location of both the MMF.P and MMF.S turned out to be significantly anterior relative to the sources of the M100. The increased stimulus repetition in the paired tone condition (two times more stimuli than in the single tone condition) lead to a strong suppression of the field amplitude and of the dipole moment of the M100, while this effect could not be seen for the MMF. The data demonstrate a fundamental difference between the processes reflected by the M100 and the MMF: while the M100 represents the processing of every individual tone, the MMF reflects the change detection of the paired stimuli as unitary events, forming a perceptual group. The different sources of the MMF.P and MMF.S also support an integrated processing of the paired stimuli.

[Is the recent decrease in cholesterolemia in the Czech Republic convincing evidence?]. / Je nedávný pokles cholesterolémie v Ceské republice prukazný?

BACKGROUND: The objective of the study was to evaluate the 8-year trend of serum cholesterol levels in six districts of the Czech Republic, to assess whether the reduction of mean values of total cholesterol recorded during the period between 1985 and 1992 was convincing and to discuss possible causes and consequences of this development. METHODS AND RESULTS: Three cross-sectional surveys of risk factors were implemented in independent random 1% samples of the population aged 25-64 years. In 1985 1256 men (respondence rate 81.5%) and 1317 women (85%) were examined, In 1988 1357 men (85.2%) and 1412 women (88.4%), in 1992 1142 men (73.2%) and 1211 women (76.7%). A detailed check of the deviations in estimations during different time intervals from reference values provided evidence that the analytical method did not have an impact on the revealed changes. In men the mean total cholesterol level was 6.21 (95% confidence limit 6.14-6.28 mmol/l in 1985; 6.29 (6.23-6.35) mmol/l in 1988; 5.99 (5.91-6.06) mmol/l in 1992. In women the mean value of the total cholesterol level was 6.19 (6.12-6.25) mmol/l in 1985; 6.23 (6.17-6.30) mmol/l in 1988; 5.95 (5.88-6.02) mmol/l in 1992. According to variance analysis (ANOVA) the serum cholesterol in 1992 was lower by 0.22 mmol/l (p < 0.0001) than in 1985 and by 0.28 mmol/l (p < 0.0001) lower than in 1988. The drop of cholesterol between 1988-1992 may have been caused by dietary changes recorded in the population. According to nationwide data after 1990 there was a marked drop of the consumption of meat and meat products, milk and dairy products and animal fats, while the consumption of vegetable fats increased. Despite these dietary improvements, in six districts in 1992 fats accounted for 37% of the energy intake, the P/S ratio was only 0.41 in men and 0.46 in women. In these districts in 1992 and 1993 a decline of the standardized mortality rate from IHD in men was recorded. CONCLUSIONS: During an eight-year period the mean serum cholesterol level of men and women decreased significantly in six districts of the Czech Republic. This change was probably associated with a restricted intake of foods which have an impact on the serum cholesterol level.

Neurophysiological correlate of the auditory after-image ('Zwicker tone').

The 'Zwicker tone' (ZT) is an auditory after-image that can be evoked most effectively when a band-suppressed noise (relative width of gap 1/3 octave) presented for a certain period of time has been switched off. The sensation of this purely monaural phenomenon is that of a pure tone with a frequency corresponding to the center frequency of the gap and an equivalent level of 10-15 dB above auditory threshold. The sensation decays gradually; it may last as long as 10 s depending on how long the evoking noise was presented. The search for a physiological correlate has been futile so far, probably because the search was confined to more peripheral levels of the auditory system (inferior colliculus). A neuromagnetic study was performed in normal-hearing subjects in order to look for a neurophysiological correlate of the ZT in the auditory cortex. With a stimulation paradigm especially designed for this study, we have been able to isolate poststimulus activity which appears to be related to the ZT and which originates in the supratemporal auditory cortex. It is a sustained neuromagnetic activity that shows a clear-cut dipolar field distribution, and it appears that this activity has certain similarities with the tone-evoked auditory sustained response. The hypothesis is put forward that during the sensation of the ZT a process takes place in the auditory cortex which is similar to that underlying the sustained response, and which gives rise to the sensation of the ZT. In contrast to the sustained response, however, which is due to neural activity evoked by an external acoustic stimulus, the sustained activity associated with the ZT is due to a temporary absolute or relative reduction of neural activity originating from those regions in which the ZT exciting stimulus caused an adaptation. These differences in neural activity cannot be distinguished by the auditory system from a corresponding external acoustic signal. Preliminary studies in patients suffering from tonal tinnitus yielded results which exhibit a certain similarity with those obtained in the ZT experiment.

Magnetic imaging in human classical conditioning.

Magnetoencephalography (MEG) was recorded during aversive classical conditioning in an attempt to elucidate the temporal coding of primary somatosensory cortex (SI) activation previously found with positron emission tomography. Four healthy volunteers participated in the experiment. The reinforced conditioned stimulus was displayed on a screen for 2 s, and as it disappeared an unconditioned electric shock to the right middle finger followed. A control stimulus, not paired with a shock was also presented. With MEG, we observed a conditioned magnetic response located in the SI. The conditioned response predated the shock presentation and is interpreted as evidence for functional control of nociception mediated by corticothalamic projections.

[Changes in the cardiovascular risk profile of the population of the Czech Republic--MONICA 1992]. / Zmeny v kardiovaskulárním rizikovém profilu obyvatelstva Ceské republiky--MONIKA 1992.

BACKGROUND: The cardiovascular risk profile of the population in the Czech Republic is unfavourable, the mortality of the population from cardiovascular diseases is among the highest in the world. The objective of the present work was to compare the prevalence of the most serious risk factors in 1988 and 1992 and to find out whether the change of the political and economic system in 1989 had an impact on the risk profile of the population. Within the framework of the international WHO project MONICA independent 1% random population samples, age bracket 25-64 years, were examined in six districts of the Czech Republic. METHODS AND RESULTS: In 1988 1,357 men (response rate 85.5%) and 1,412 women (88.4%) were examined; in 1992 1,139 men (71.2%) and 1,214 women (75.0%) attended the examination. The prevalence of smokers (regular consumption of more than 1 cigarette per day) did not differ significantly in men: 41.8% in 1988, 40.3% in 1992 nor in women: 25.3%-24.1%. Also the prevalence of elevated blood pressure levels (BPs > 21.3 and/or BPd > 12.7 kPa) did not reveal a significant difference neither in men: 19.1%-20.4% nor in women 14.0%-15.0%. The prevalence of hypercholesterolaemia (total cholesterol > 6.5 mmol/l) was in 1992 significantly lower than in 1988--in men by 9% (39.6%-30.6%, p < 0.001) and in women by 6.3% (36.3%-30.0%, p < 0.001). Also in the prevalence of obesity (BMI men > 30, women > 29) a significant drop was recorded in men by 5.2% (23.8%-18.6%, p < 0.01) in women by 5.1% (33.3%-28.2%, p < 0.01). CONCLUSIONS: The probable reason for this partial improvement of the risk profile in 1992, as compared with data in 1988, are dietary changes which may be the result of the introduced market economy and global transformation of society after the political change in 1989.

The magnetic counterpart of the contingent negative variation.

The magnetic counterpart of the CNV, the contingent magnetic variation (CMV), was investigated in an Go/No Go design: subjects moved their index finger to the offset of a 4 sec tone of a certain frequency in the Go condition and were asked not to move during presentation of a 4 sec tone of different frequency in the No Go condition. During the preparatory interval, both the CMV and the electrical wave form followed a similar time course and both produced an equally pronounced statistical difference between conditions (Go and No Go). Compared to the variability in the auditory evoked fields, the CMV showed considerably more variance in the field distribution across subjects. The polarity reversal across the temporal surface of the head and the pronounced amplitudes over inferior temporal areas led us to conclude that a significant temporal activity contributes to both the late and the early CMV. However, neither for the early nor for the late CMV component did a single equivalent dipole prove to be a satisfying model. The data are consistent with the suggestion that the earlier as well as the later aspects of the CMV are fed through distributed sources in motoric, sensory and association areas, a distribution with considerable intersubject variability.

The auditory evoked sustained field: origin and frequency dependence.

A sound lasting for several seconds is known to elicit a baseline shift in electrical and magnetic records. We have studied the dependence of the magnetic field distribution of this "per-stimulatory" sustained field (SF) on tone frequency. Tone bursts of 2 sec duration and 60 dB nHL intensity were presented to 11 subjects at varying interstimulus intervals between 5 and 7 sec. The carrier frequencies of 250, 1000 and 4000 Hz varied randomly from trial to trial. The field distributions obtained are consistent with the view that the auditory evoked sustained field activity originates in the supratemporal cortex. Differences in the locations of equivalent current dipoles of the SF from those of the M100 wave of the slow auditory evoked field are consistent across subjects. The SF source locations corresponding to stimulus frequencies over an extended frequency range are arranged in a tonotopic manner and support the idea that the sources of the M100 and the SF are current dipole sheets located on the superior surface of the primary auditory cortex.