A1.40 Adiponektin and resistin levels in pregnant patients with rheumatoid arthritis

BACKGROUND Pregnancy induces a modulation of the maternal immune system in order to install tolerance towards the semiallogeneic fetus. This change of the maternal immune systems influences some autoimmune diseases such as rheumatoid arthritis (RA) in a positive way. Our previous study showed that genes of the adipocytokine pathway were differently regulated by pregnancy as well as by RA. The objective of this study was to analyse the association between pregnancy induced improvement of RA and changes of adipocytokine levels. MATERIAL AND METHODS Adiponectin and resistin levels were measured in sera of pregnant (n = 29) and non-pregnant (n = 24) RA patients as well as in pregnant (n = 26) and non-pregnant (n = 9) healthy controls by ELISA. Pregnant RA patients were analysed before conception, once at each trimester and 8 weeks postpartum. Disease activity was measured by CRP and DAS28-CRP. RESULTS Resistin levels were higher in non-pregnant RA patients than in healthy controls. Resistin levels increased during pregnancy and decreased postpartum in both healthy subjects and RA patients. However, RA patients with active disease during pregnancy showed higher resistin levels at the third trimester than healthy women. There was a positive correlation between resistin levels and CRP. Adiponektin levels increased at the second trimester of pregnancy and decreased thereafter in both healthy subject and RA patients. There was no difference between patients and healthy subjects. Adiponektin levels of RA patients negatively correlated with CRP. CONCLUSION Pregnancy induces an increase of both the resistin and the adiponectin levels. Resistin levels are further influenced by active disease. By contrast, the increase of the adiponectin levels at the second trimester might play a role in the modulation of disease activity of RA.

Microbial communities in the respiratory tract of patients with interstitial lung disease

Background Molecular methods based on phylogenetic differences in the 16S rRNA gene are able to characterise the microbiota of the respiratory tract in health and disease. Objectives Our goals were (1) to characterise bacterial communities in lower and upper airways of patients with interstitial lung disease (ILD) and (2) to compare the results with the microbiota of patients with Pneumocystis pneumonia (PCP) and normal controls. Methods We examined the upper and lower respiratory tract of 18 patients with ILD of whom 5, 6, and 7 had idiopathic interstitial pneumonia (IIP), non-IIP and sarcoidosis, respectively. In addition, six immune-compromised patients with PCP and nine healthy subjects were included as controls. Exclusion criteria were recent bacterial/viral respiratory tract infection, HIV-positivity and subjects receiving antibiotic therapy. Bronchoalveolar lavage fluid and oropharyngeal swabs were simultaneously collected, and microbiota was characterised by ultra-deep 16S rRNA gene sequencing. Results The microbiota in lower airways of the majority of patients (30; 90%) primarily consisted of Prevotellaceae, Streptococcaceae and Acidaminococcaceae. α and β diversity measurements revealed no significant differences in airway microbiota composition between the five different groups of patients. Comparison of bacterial populations in upper and lower respiratory tract showed significant topographical discontinuities for 7 (23%) individuals. Conclusions IIP, non-IIP and sarcoidosis are not associated with disordered airway microbiota and a pathogenic role of commensals in the disease process is therefore unlikely. Nevertheless, molecular analysis of the topographical microbiota continuity along the respiratory tract may provide additional information to assist management of individual patients.

On the use of Cramér-Rao minimum variance bounds for the design of magnetic resonance spectroscopy experiments

Localized Magnetic Resonance Spectroscopy (MRS) is in widespread use for clinical brain research. Standard acquisition sequences to obtain one-dimensional spectra suffer from substantial overlap of spectral contributions from many metabolites. Therefore, specially tuned editing sequences or two-dimensional acquisition schemes are applied to extend the information content. Tuning specific acquisition parameters allows to make the sequences more efficient or more specific for certain target metabolites. Cramér-Rao bounds have been used in other fields for optimization of experiments and are now shown to be very useful as design criteria for localized MRS sequence optimization. The principle is illustrated for one- and two-dimensional MRS, in particular the 2D separation experiment, where the usual restriction to equidistant echo time spacings and equal acquisition times per echo time can be abolished. Particular emphasis is placed on optimizing experiments for quantification of GABA and glutamate. The basic principles are verified by Monte Carlo simulations and in vivo for repeated acquisitions of generalized two-dimensional separation brain spectra obtained from healthy subjects and expanded by bootstrapping for better definition of the quantification uncertainties.

Metabolic control in children and adolescents with diabetes mellitus type I in Berne: a cross-sectional study.

AIMS/HYPOTHESIS In diabetes mellitus type I, good glycaemic control is crucial in preventing long-term diabetic complications. The aim of this study was to determine the current level of metabolic control in children and adolescents in our diabetes outpatient clinic at the University Children's Hospital, Berne. Furthermore, the impact of different factors such as age, pubertal stage, sex, duration of diabetes and insulin regimen on glycaemic control was studied. METHODS In a cross-sectional, prospective study 168 children and adolescents with type I diabetes mellitus (f:m = 87:81; prepubertal 48 [mean age 4.4 years, mean duration of diabetes 2.8 years]; pubertal 120 [mean age 9.4 years; mean duration of diabetes 5.2 years]) were studied for three months. Clinical data and HbA1c levels (latex immunoagglutination test) were recorded, statistically analysed and compared with the international literature. RESULTS In our type I diabetic children and adolescents the overall HbA1c was 8.07 +/- 1.15% (mean +/- SD; test-specific norm for healthy subjects: 4.1-6.1%). Glycaemic control was significantly worse in the pubertal group compared to the prepubertal (HbA1c 8.22 +/- 1.25% vs. 7.81 +/- 0.87%; p < 0.01). In addition, we found better metabolic control in patients with duration of diabetes below 2 years in children and adolescents (HbA1c prepubertal < 2 years: 7.45 +/- 0.67% vs. > 2 years: 8.05 +/- 0.93%, p < 0.05; pubertal < 2 years: 7.62 +/- 0.75% vs. > 2 years: 8.31 +/- 1.29%, p < 0.005). Importantly, sex and insulin regimen did not significantly influence glycaemic control. CONCLUSION/INTERPRETATION The current level of metabolic control in our children and adolescents with diabetes mellitus type I is comparable to the glycaemic control of the intensively treated adolescent group of the DCCT-study, in whom decreased risk of long-term diabetic complications was found. In contrast, our patients were intensively treated in terms of frequent contacts with the diabetes team, but were not necessarily on an intensified insulin regimen. The impact of biopsychosocial support from multidisciplinary diabetes team on good metabolic control in children and adolescents with type I diabetes mellitus and their families seems to be very important.

Low single dose gabapentin does not affect prefrontal and occipital gamma-aminobutyric acid concentrations

The γ-aminobutyric acid (GABA) system has been proposed as a target for novel antidepressant and anxiolytic treatments. Emerging evidence suggests that gabapentin (GBP), an anticonvulsant drug that significantly increases brain GABA levels, is effective in the treatment of anxiety disorders. The current study was designed to measure prefrontal and occipital GABA levels in medication-free healthy subjects after taking 0 mg, 150 mg and 300 mg GBP. Subjects were scanned on a 3T scanner using a transmit-receive head coil that provided a relatively homogenous radiofrequency field to obtain spectroscopy measurement in the medial prefrontal (MPFC) and occipital cortex (OCC). There was no dose-dependent effect of GBP on GABA levels in the OCC or MPFC. There was also no effect on Glx, choline or N-acetyl-aspartate concentrations. The previously reported finding of increased GABA levels after GBP treatment is not evident for healthy subjects at the dose of 150 and 300 mg. As a result, if subjects are scanned on a 3T scanner, low dose GPB is not useful as an experimental challenge agent on the GABA system.

Repeatability analysis of global and local metrics of brain structural networks

Computational network analysis provides new methods to analyze the human connectome. Brain structural networks can be characterized by global and local metrics that recently gave promising insights for diagnosis and further understanding of neurological, psychiatric and neurodegenerative disorders. In order to ensure the validity of results in clinical settings the precision and repeatability of the networks and the associated metrics must be evaluated. In the present study, nineteen healthy subjects underwent two consecutive measurements enabling us to test reproducibility of the brain network and its global and local metrics. As it is known that the network topology depends on the network density, the effects of setting a common density threshold for all networks were also assessed. Results showed good to excellent repeatability for global metrics, while for local metrics it was more variable and some metrics were found to have locally poor repeatability. Moreover, between subjects differences were slightly inflated when the density was not fixed. At the global level, these findings confirm previous results on the validity of global network metrics as clinical biomarkers. However, the new results in our work indicate that the remaining variability at the local level as well as the effect of methodological characteristics on the network topology should be considered in the analysis of brain structural networks and especially in networks comparisons.

Variability between laboratories performing coagulation tests with identical platforms: a nationwide evaluation study.

BACKGROUND While the assessment of analytical precision within medical laboratories has received much attention in scientific enquiry, the degree of as well as the sources causing variation between them remains incompletely understood. In this study, we quantified the variance components when performing coagulation tests with identical analytical platforms in different laboratories and computed intraclass correlations coefficients (ICC) for each coagulation test. METHODS Data from eight laboratories measuring fibrinogen twice in twenty healthy subjects with one out of 3 different platforms and single measurements of prothrombin time (PT), and coagulation factors II, V, VII, VIII, IX, X, XI and XIII were analysed. By platform, the variance components of (i) the subjects, (ii) the laboratory and the technician and (iii) the total variance were obtained for fibrinogen as well as (i) and (iii) for the remaining factors using ANOVA. RESULTS The variability for fibrinogen measurements within a laboratory ranged from 0.02 to 0.04, the variability between laboratories ranged from 0.006 to 0.097. The ICC for fibrinogen ranged from 0.37 to 0.66 and from 0.19 to 0.80 for PT between the platforms. For the remaining factors the ICC's ranged from 0.04 (FII) to 0.93 (FVIII). CONCLUSIONS Variance components that could be attributed to technicians or laboratory procedures were substantial, led to disappointingly low intraclass correlation coefficients for several factors and were pronounced for some of the platforms. Our findings call for sustained efforts to raise the level of standardization of structures and procedures involved in the quantification of coagulation factors.

Focal white matter changes in spasmodic dysphonia: a combined diffusion tensor imaging and neuropathological study.

Spasmodic dysphonia is a neurological disorder characterized by involuntary spasms in the laryngeal muscles during speech production. Although the clinical symptoms are well characterized, the pathophysiology of this voice disorder is unknown. We describe here, for the first time to our knowledge, disorder-specific brain abnormalities in these patients as determined by a combined approach of diffusion tensor imaging (DTI) and postmortem histopathology. We used DTI to identify brain changes and to target those brain regions for neuropathological examination. DTI showed right-sided decrease of fractional anisotropy in the genu of the internal capsule and bilateral increase of overall water diffusivity in the white matter along the corticobulbar/corticospinal tract in 20 spasmodic dysphonia patients compared to 20 healthy subjects. In addition, water diffusivity was bilaterally increased in the lentiform nucleus, ventral thalamus and cerebellar white and grey matter in the patients. These brain changes were substantiated with focal histopathological abnormalities presented as a loss of axonal density and myelin content in the right genu of the internal capsule and clusters of mineral depositions, containing calcium, phosphorus and iron, in the parenchyma and vessel walls of the posterior limb of the internal capsule, putamen, globus pallidus and cerebellum in the postmortem brain tissue from one patient compared to three controls. The specificity of these brain abnormalities is confirmed by their localization, limited only to the corticobulbar/corticospinal tract and its main input/output structures. We also found positive correlation between the diffusivity changes and clinical symptoms of spasmodic dysphonia (r = 0.509, P = 0.037). These brain abnormalities may alter the central control of voluntary voice production and, therefore, may underlie the pathophysiology of this disorder.

Left posterior parietal theta burst stimulation affects gestural imitation regardless of semantic content.

OBJECTIVE Neuro-imaging studies have suggested that the ability to imitate meaningless and meaningful gestures may differentially depend on superior (SPL) and inferior (IPL) parietal lobule. Therefore, we hypothesized that imaging-guided neuro-navigated continuous theta burst stimulation (cTBS) over left SPL mainly affects meaningless and over left IPL predominantly meaningful gestures. METHODS Twelve healthy subjects participated in this study. High resolution structural MRI was used for imaging guided neuro-navigation cTBS. Participants were targeted with one train of cTBS in three experimental sessions: sham stimulation over vertex and real cTBS over left SPL and IPL, respectively. An imitation task, including 24 meaningless and 24 meaningful gestures, was performed 'offline'. RESULTS cTBS over both left IPL and SPL significantly interfered with gestural imitation. There was no differential effect of SPL and IPL cTBS on gesture type (meaningless versus meaningful). CONCLUSIONS Our findings confirm that left posterior parietal cortex plays a predominant role in gestural imitation. However, the hypothesis based on the dual route model suggesting a differential role of SPL and IPL in the processing of meaningless and meaningful gestures could not be confirmed. SIGNIFICANCE Left SPL and IPL play a common role within the posterior-parietal network in gestural imitation regardless of semantic content.

A cardiovascular mathematical model of graded head-up tilt

A lumped parameter model of the cardiovascular system has been developed and optimized using experimental data obtained from 13 healthy subjects during graded head-up tilt (HUT) from the supine position to [Formula: see text]. The model includes descriptions of the left and right heart, direct ventricular interaction through the septum and pericardium, the systemic and pulmonary circulations, nonlinear pressure volume relationship of the lower body compartment, arterial and cardiopulmonary baroreceptors, as well as autoregulatory mechanisms. A number of important features, including the separate effects of arterial and cardiopulmonary baroreflexes, and autoregulation in the lower body, as well as diastolic ventricular interaction through the pericardium have been included and tested for their significance. Furthermore, the individual effect of parameter associated with heart failure, including LV and RV contractility, baseline systemic vascular resistance, pulmonary vascular resistance, total blood volume, LV diastolic stiffness and reflex gain on HUT response have also been investigated. Our fitted model compares favorably with our experimental measurements and published literature at a range of tilt angles, in terms of both global and regional hemodynamic variables. Compared to the normal condition, a simulated congestive heart failure condition produced a blunted response to HUT with regards to the percentage changes in cardiac output, stroke volume, end diastolic volume and effector response (i.e., heart contractility, venous unstressed volume, systemic vascular resistance and heart rate) with progressive tilting.

How useful is the ultrastructural study of the cilia of the respiratory tract in the diagnosis of an immotile cilia syndrome?

The immotile cilia syndrome (ICS) comprises a range of congenital defects of the ciliary apparatus most probably transmitted by autosomal recessive inheritance. Because cilia occur mainly in the respiratory and genital tract, the clinical symptoms of ICS are most commonly chronic sinusitis, bronchitis, bronchiectasis and male sterility. The syndrome can be associated with a situs inversus and is then called Kartagener's syndrome. We studied the ciliary ultrastructure in airway biopsies of 5 patients suffering from chronic upper and lower respiratory tract infections. With the single exception of one female patient with confirmed ICS diagnosis (Kartagener's syndrome) the etiology of the recurrent infections was unknown. The following ciliary defects were observed: missing dynein arms, radial spoke defects, missing nexin links, microtubular transpositions, compound cilia, supernumerary, absent, or incomplete microtubules, lack of ciliary orientation and various abnormal patterns of microtubular arrangement. In no instance did a patient show only a single anomaly; defects were always combined. Missing dynein arms, radial spoke defects and microtubular transpositions have frequently been described as lesions specific for ICS. Whenever these lesions were found simultaneously in both the respiratory and genital tracts, their genetic origin cannot be doubted. In our confirmed ICS patient the outer dynein arms were not missing but were reduced in number and length in a large number of cilia. The biopsy was, however, obtained from the heavily infected maxillary sinus and it is known that inflammation can lead to a loss of dynein arms. In the light of our investigations and of a review of the published cases of ciliary anomalies, it is concluded that none of the above defects in itself is specific for ICS. They may all occur as secondary lesions or sporadically as varieties in otherwise healthy subjects. It therefore appears questionable whether ICS can be diagnosed from the ciliary ultrastructure of a single airway biopsy. Assessment of ICS cannot be based simply on the ultrastructural demonstration of a particular ciliary defect, but necessitates additional considerations particularly regarding the origin of the biopsy, the sampling procedures and quantitation of defects. It appears necessary to investigate samples from different parts of the airways and quantitatively analyze the prominent lesions.

Physiological effects of mechanical pain stimulation at the lower back measured by functional near-infrared spectroscopy and capnography

The aim was to investigate the effect of mechanical pain stimulation at the lower back on hemodynamic and oxygenation changes in the prefrontal cortex (PFC) assessed by functional near-infrared spectroscopy (fNIRS) and on the partial pressure of end-tidal carbon dioxide ( PetCO 2) measured by capnography. 13 healthy subjects underwent three measurements (M) during pain stimulation using pressure pain threshold (PPT) at three locations, i.e., the processus spinosus at the level of L4 (M1) and the lumbar paravertebral muscles at the level of L1 on the left (M2) and the right (M3) side. Results showed that only in the M2 condition the pain stimulation elicited characteristic patterns consisting of (1) a fNIRS-derived decrease in oxy- and total hemoglobin concentration and tissue oxygen saturation, an increase in deoxy-hemoglobin concentration, (2) a decrease in the PetCO 2 response and (3) a decrease in coherence between fNIRS parameters and PetCO 2 responses in the respiratory frequency band (0.2-0.5 Hz). We discuss the comparison between M2 vs. M1 and M3, suggesting that the non-significant findings in the two latter measurements were most likely subject to effects of the different stimulated tissues, the stimulated locations and the stimulation order. We highlight that PetCO 2 is a crucial parameter for proper interpretation of fNIRS data in experimental protocols involving pain stimulation. Together, our data suggest that the combined fNIRS-capnography approach has potential for further development as pain monitoring method, such as for evaluating clinical pain treatment.

Changes in cerebral hemodynamics and oxygenation induced by different speech tasks – an assessment by combining functional near‐infrared spectroscopy and capnography

Introduction In several studies, we found that during guided rhythmic speech exercises, a decrease in cerebral hemodynamics and oxygenation occurred as the result of a decrease in the partial pressure of carbon dioxide in the arterial blood (PaCO2) during speaking. To further explore the effect of PaCO2 variations on cerebral hemodynamics and oxygenation, the aim of the present study was to investigate the impact of spoken, inner and heard speech tasks on these parameters. Material and Methods Speech tasks included recitation or inner recitation or listening to hexameter, alliteration, prose, or performing mental arithmetic. The following physiological parameters were measured: tissue oxygen saturation (StO2) and absolute concentrations of oxyhemoglobin, deoxyhemoglobin, total hemoglobin (over the left and right anterior prefrontal cortex, using an ISS OxiplexTS frequency domain near-infrared spectrometer) and end-tidal CO2 (PETCO2; using Nellcor N1000 and Datex NORMOCAP capnographs). Statistical analysis was applied to the differences between baseline, 2 tasks, and 3 post-baseline periods. Data of 3 studies with 24, 7 and 29 healthy subjects, respectively, were combined, and linear regression analyses were calculated. Results Linear regression analyses revealed significant relations between changes in oxyhemoglobin, deoxyhemoglobin, total hemoglobin or StO2 and the participants’ age, the baseline PETCO2 or certain speech tasks. While hexameter verses affected changes during the tasks, alliteration verses only affected changes during the recovery phase. Discussion and Conclusion The observed effects in hemodynamics and oxygenation indicate a combination of neurovascular coupling (increased neuronal activity leading to an increase in the cerebral metabolic rate of oxygen resulting in an increase in cerebral flood flow/volume) and CO2 reactivity (increased breathing during speech tasks causing a decrease in PaCO2 leading to vasoconstriction and decrease in cerebral blood flow). The neurovascular coupling characteristics are task-dependent. References Scholkmann F, Gerber U, Wolf M, Wolf U. End-tidal CO2: An important parameter for a correct interpretation in functional brain studies using speech tasks. Neuroimage 2013;66:71-79. Scholkmann F, Wolf M, Wolf U. The effect of inner speech on arterial CO2, cerebral hemodynamics and oxygenation – A functional NIRS study. Adv Exp Med Biol 2013;789:81-87.

The Frontal Eye Field Is Involved in Visual Vector Inversion in Humans – A Theta Burst Stimulation Study

In the antisaccade task, subjects are requested to suppress a reflexive saccade towards a visual target and to perform a saccade towards the opposite side. In addition, in order to reproduce an accurate saccadic amplitude, the visual saccade vector (i.e., the distance between a central fixation point and the peripheral target) must be exactly inverted from one visual hemifield to the other. Results from recent studies using a correlational approach (i.e., fMRI, MEG) suggest that not only the posterior parietal cortex (PPC) but also the frontal eye field (FEF) might play an important role in such a visual vector inversion process. In order to assess whether the FEF contributes to visual vector inversion, we applied an interference approach with continuous theta burst stimulation (cTBS) during a memory-guided antisaccade task. In 10 healthy subjects, one train of cTBS was applied over the right FEF prior to a memory-guided antisaccade task. In comparison to the performance without stimulation or with sham stimulation, cTBS over the right FEF induced a hypometric gain for rightward but not leftward antisaccades. These results obtained with an interference approach confirm that the FEF is also involved in the process of visual vector inversion.

Adaption of cardio-respiratory balance during day-rest compared to deep sleep—An indicator for quality of life?

Heart rate and breathing rate fluctuations represent interacting physiological oscillations. These interactions are commonly studied using respiratory sinus arrhythmia (RSA) of heart rate variability (HRV) or analyzing cardiorespiratory synchronization. Earlier work has focused on a third type of relationship, the temporal ratio of respiration rate and heart rate (HRR). Each method seems to reveal a specific aspect of cardiorespiratory interaction and may be suitable for assessing states of arousal and relaxation of the organism. We used HRR in a study with 87 healthy subjects to determine the ability to relax during 5 day-resting periods in comparison to deep sleep relaxation. The degree to which a person during waking state could relax was compared to somatic complaints, health-related quality of life, anxiety and depression. Our results show, that HRR is barely connected to balance (LF/HF) in HRV, but significantly correlates to the perception of general health and mental well-being as well as to depression. If relaxation, as expressed in HRR, during day-resting is near to deep sleep relaxation, the subjects felt healthier, indicated better mental well-being and less depressive moods.