In vivo biomarkers of structural and functional brain development and aging in humans.

Brain aging is a major determinant of aging. Along with the aging population, prevalence of neurodegenerative diseases is increasing, therewith placing economic and social burden on individuals and society. Individual rates of brain aging are shaped by genetics, epigenetics, and prenatal environmental. Biomarkers of biological brain aging are needed to predict individual trajectories of aging and the risk for age-associated neurological impairments for developing early preventive and interventional measures. We review current advances of in vivo biomarkers predicting individual brain age. Telomere length and epigenetic clock, two important biomarkers that are closely related to the mechanistic aging process, have only poor deterministic and predictive accuracy regarding individual brain aging due to their high intra- and interindividual variability. Phenotype-related biomarkers of global cognitive function and brain structure provide a much closer correlation to age at the individual level. During fetal and perinatal life, autonomic activity is a unique functional marker of brain development. The cognitive and structural biomarkers also boast high diagnostic specificity for determining individual risks for neurodegenerative diseases.

Association Between Systemic Inflammation, Carotid Arteriosclerosis, and Autonomic Dysfunction.

Systemic inflammation is associated with arteriosclerotic disease progression and worse stroke outcome in patients with carotid arteriosclerotic disease. We hypothesize that systemic inflammation is mediated by impaired carotid baroreceptor and chemoreceptor function induced by carotid arteriosclerosis rather than by the generalized inflammatory arteriosclerotic process.Heart rate variability (HRV), serum levels of inflammatory markers, demographic and life style factors, and concomitant diseases with potential impact on systemic inflammation were determined in 105 patients with asymptomatic carotid stenosis of varying degree. Multivariate linear regression analyses were performed to ascertain independent determinants of carotid stenosis severity, autonomic function, and inflammation.Systemic inflammation (C-reactive protein, beta = .255; P = .014), age (beta = .232; P < .008), and arterial hypertension (beta = .206; P = .032) were associated with carotid stenosis severity. Only carotid stenosis severity and not generalized arteriosclerotic disease, concomitant diseases (arterial hypertension, diabetes mellitus, dyslipidemia, hypothyroidism), life style factors (smoking, obesity), or age was associated with a reduction in vagal tone (HRV HF band power beta = - .193; P < 0.049). Systemic inflammation was related to a reduction in vagal tone (HRV HF band power, beta = - .214; P = .031), and not to generalized arteriosclerotic disease, concomitant diseases (arterial hypertension, diabetes mellitus, dyslipidemia), life style factors (smoking, obesity), and age.In conclusion, systemic inflammation is associated with carotid rather than with generalized arteriosclerotic disease. The association between systemic inflammation and carotid arteriosclerosis is mediated by a reduction in vagal tone which indicates a major role of carotid arteriosclerosis-mediated autonomic dysfunction in the pathogenesis of systemic inflammation in arteriosclerotic disease.

[Intensive care aspects of autoimmune encephalitis]. / Intensivmedizinische Aspekte der Autoimmunenzephalitis.

Autoimmune encephalitis is a rare, rapidly progressive and potentially severe inflammatory brain disease, usually mediated by autoantibodies. Frequently, the affected patients go through various phases of the disease with prodromi, neuropsychological abnormalities, severe neurological and autonomic disorders and usually long reconvalescence. In up to 85% of patients intensive care treatment is necessary, especially in the group of anti-NMDA receptor encephalitis (NMDA-RE). Typical problems during ICU stay include: severe qualitative and quantitative disturbances of consciousness, autonomic dysfunction, epileptic seizures/epileptic status, treatment-refractory movement disorders, as well as ventilation and weaning problems requiring tracheotomy. But also ethical conflicts and general ICU complications such as sepsis, the need for resuscitation, as well as surgical and psychiatric complications occur. The outcome is highly heterogeneous with a range from complete recovery to the most severe, persistent disorders of consciousness with extensive care and death. Mortality data also vary at between 12% and 40%. Patients requiring mechanical ventilation and tracheostomy and with sepsis and autonomic dysfunction are prone to worse outcomes. A large part of the presented data refers to a recently published multicenter, Germany-wide retrospective cohort study and brought into the context of existing literature.

Cause or effect: Altered brain and network activity in cervical dystonia is partially normalized by botulinum toxin treatment.

BACKGROUND: Idiopathic cervical dystonia (CD) is a chronic movement disorder characterized by impressive clinical symptoms and the lack of clear pathological findings in clinical diagnostics and imaging. At present, the injection of botulinum toxin (BNT) in dystonic muscles is an effective therapy to control motor symptoms and pain in CD. OBJECTIVES: We hypothesized that, although it is locally injected to dystonic muscles, BNT application leads to changes in brain and network activity towards normal brain function. METHODS: Using 3 T functional MR imaging along with advanced analysis techniques (functional connectivity, Granger causality, and regional homogeneity), we aimed to characterize brain activity in CD (17 CD patients vs. 17 controls) and to uncover the effects of BNT treatment (at 6 months). RESULTS: In CD, we observed an increased information flow within the basal ganglia, the thalamus, and the sensorimotor cortex. In parallel, some of these structures became less responsive to regulating inputs. Furthermore, our results suggested an altered somatosensory integration. Following BNT administration, we noted a shift towards normal brain function in the CD patients, especially within the motor cortex, the somatosensory cortex, and the basal ganglia. CONCLUSION: The changes in brain function and network activity in CD can be interpreted as related to the underlying cause, the effort to compensate or a mixture of both. Although BNT is applied in the last stage of the cortico-neuromuscular pathway, brain patterns are shifted towards those of healthy controls.

[Preoperative conditioning in ageing patients-gerontosurgery]. / Präoperative Konditionierung im Alter ­ Gerontochirurgie.

Adapting the daily hospital routine to changes in the aging structure of society and the patients will be one of the main challenges for surgeons in the coming years. Important factors regarding the outcome of aging patients will be preoperative conditioning, specific age-adapted surgical strategies and the organization of the hospital infrastructure. Nutritional protocols and liquid intake schedules should be taken into account as well as cognitive assessment tools and strategies to protect aging patients from postoperative delirium. The importance of changes in metabolism and the concomitant comorbidities are very similar in most specialty disciplines. The lack of a clear and widely accepted definition of biological age and the missing adaptations of, e. g. complication scores, currently exacerbate the compilation of a resilient survey. In the absence of a reimbursement-system for geriatric medicine it will be very difficult to achieve the necessary structural changes in the treatment regimens for older patients. The establishment of the necessary surgical treatment adapted to the needs of older patients therefore remains a challenging task.

[How many potential organ donors are there really? : Retrospective analysis of why determination of irreversible loss of brain function was not performed in deceased patients with relevant brain damage]. / Wie viele potenzielle Organspender gibt es wirklich? : Retrospektive Analyse zu nichterfolgter Diagnostik des irreversiblen Hirnfunktionsausfalls bei verstorbenen Patienten mit relevanter Hirnschädigung.

BACKGROUND: No systematic study has previously been undertaken in Germany to ascertain why irreversible brain death determination (BDD) has not been carried out. OBJECTIVE: A comprehensive analysis of reasons for unperformed BDD in deceased patients with acute, severe brain damage could improve the identification of potential organ donors. METHOD: Using the Transplantcheck program of the German Organ Transplantation Foundation (DSO) an analysis of the data from 2016 was undertaken in participating hospitals in Saxony, Saxony-Anhalt and Thuringia (Region East of the DSO), regarding why a BDD was not initiated in deceased patients with primary or secondary brain damage. RESULTS: In 128 of the 144 Region East hospitals, 7889 deceased patients with primary or secondary brain damage were detected. In 7389 patients a BDD was out of the question for a variety of reasons. In 232 patients organ donation was not considered due to an advance directive. In 195 cases treatment was limited based on the patient's infaust neurological prognosis without the possibility of organ donation being discussed with relatives. In 73 cases initiation of BDD was indicated but not performed. CONCLUSION: The number of potential organ donors in Region East of the DSO could be significantly increased by identifying patients where BDD is indicated. By consistent evaluation of patients' wills in terms of organ donation before treatment is withdrawn in patients with poor neurological prognosis, additional potential organ donors could be identified. Furthermore, involving neurointensive care physicians in the care of all patients with brain damage could improve the prognostic assessment.

Motor-cognitive dual-task performance: effects of a concurrent motor task on distinct components of visual processing capacity.

Dual tasking, or the simultaneous execution of two continuous tasks, is frequently associated with a performance decline that can be explained within a capacity sharing framework. In this study, we assessed the effects of a concurrent motor task on the efficiency of visual information uptake based on the 'theory of visual attention' (TVA). TVA provides parameter estimates reflecting distinct components of visual processing capacity: perceptual threshold, visual processing speed, and visual short-term memory (VSTM) storage capacity. Moreover, goodness-of-fit values and bootstrapping estimates were derived to test whether the TVA-model is validly applicable also under dual task conditions, and whether the robustness of parameter estimates is comparable in single- and dual-task conditions. 24 subjects of middle to higher age performed a continuous tapping task, and a visual processing task (whole report of briefly presented letter arrays) under both single- and dual-task conditions. Results suggest a decline of both visual processing capacity and VSTM storage capacity under dual-task conditions, while the perceptual threshold remained unaffected by a concurrent motor task. In addition, goodness-of-fit values and bootstrapping estimates support the notion that participants processed the visual task in a qualitatively comparable, although quantitatively less efficient way under dual-task conditions. The results support a capacity sharing account of motor-cognitive dual tasking and suggest that even performing a relatively simple motor task relies on central attentional capacity that is necessary for efficient visual information uptake.

[Contribution of temozolomide chemotherapy for intramedullary grade II spinal cord astrocytomas in adults: Our experience]. / Place de la chimiothérapie de type témozolomide pour les astrocytomes intramédullaires de grade II de l'adulte : notre expérience.

INTRODUCTION: Grade II intramedullary astrocytomas are rare tumors. Despite a well-defined role of adjuvant temozolomide chemotherapy for brain gliomas, the contribution of this therapy for intramedullary gliomas is not yet clearly defined. METHOD: We retrospectively analyzed the data of 5 adult patients treated with temozolomide between 2008 and 2015 for a grade II intramedullary astrocytoma with progression after surgery. RESULTS: Five patients from 19 to 70 years of age (median, 37years) underwent a second surgery for the progression of a grade II intramedullary astrocytoma (median progression-free survival 26months [8-90]). All tumors remained grade II. Due to a second clinical or/and radiological tumor progression, the patients were treated with temozolomide after a 37months median progression-free survival (5-66). All patients received at minimum 12 cycles (mean 14 ± 5; range 12-24) of temozolomide (150-200mg/m2/day, 5days/28days). All patients were alive after a 10-year median follow-up after diagnosis (6-13). All patients were able to walk except one, who was previously in McCormick autonomy grade IV before chemotherapy. The McCormick autonomy rating after temozolomide was stable for 4 patients and improved for 1 patient. The treatment was delayed once for hematological toxicity. CONCLUSION: Temozolomide stabilized all 5 patients without any major toxicity. Based on this experience that needs to be confirmed, we consider that temozolomide should be envisaged within the therapeutic arsenal for progressive intramedullary grade II astrocytomas.

Inpatient treatment of patients with acute idiopathic peripheral facial palsy: A population-based healthcare research study.

OBJECTIVES: To determine the inpatient management for patients with acute idiopathic facial palsy (IFP) in Thuringia, Germany. DESIGN: Population-based study. SETTING: All inpatients with IFP in all hospitals with departments of otolaryngology and neurology in 2012, in the German federal state, Thuringia. MAIN OUTCOME MEASURES: Patients' characteristics and treatment were compared between departments, and the probability of recovery was tested. RESULTS: A total of 291 patients were mainly treated in departments of otolaryngology (55%) and neurology (36%). Corticosteroid treatment was the predominant therapy (84.5%). The probability to receive a facial nerve grading (odds ratio [OR=12.939; 95% confidence interval [CI]=3.599 to 46.516), gustatory testing (OR=6.878; CI=1.064 to 44.474) and audiometry (OR=32.505; CI=1.485 to 711.257) was significantly higher in otolaryngology departments, but lower for cranial CT (OR=0.192; CI=0.061 to 0.602), cerebrospinal fluid examination (OR=0.024; CI=0.006 to 0.102). A total of 131 patients (45%) showed a recovery to House-Brackmann grade≤II. A pathological stapedial reflex test (Hazard ratio [HR]=0.416; CI=0.180 to 0.959) was the only independent diagnostic predictor of worse outcome. Prednisolone dose >500 mg (HR=0.579; CI 0.400 to 0.838) and no adjuvant physiotherapy (HR=0.568; CI=0.407 to 0.794) were treatment-related predictors of worse outcome. CONCLUSIONS: Inpatient treatment of IFP seems to be highly variable in daily practice, partly depending on the treating discipline and despite the availability of evidence-based guidelines. The population-based recovery rate was worse than reported in clinical trials.

Development of somatosensory-evoked potentials in foetal sheep: effects of betamethasone.

AIM: Antenatal glucocorticoids are used to accelerate foetal lung maturation in babies threatened with premature labour. We examined the influence of glucocorticoids on functional and structural maturation of the central somatosensory pathway in foetal sheep. Somatosensory-evoked potentials (SEP) reflect processing of somatosensory stimuli. SEP latencies are determined by afferent stimuli transmission while SEP amplitudes reveal cerebral processing. METHODS: After chronic instrumentation of foetal sheep, mothers received saline (n = 9) or three courses of betamethasone (human equivalent dose of 2 × 110 µg kg-1 betamethasone i.m. 24 h apart, n = 12) at 0.7, 0.75 and 0.8 of gestational age. Trigeminal SEP were evoked prior to, 4 and 24 h after each injection and at 0.8 of gestational age before brains were histologically processed. RESULTS: Somatosensory-evoked potentials were already detectable at 0.7 of gestation age. The early and late responses N20 and N200 were the only reproducible peaks over the entire study period. With advancing gestational age, SEP latencies decreased but amplitudes remained unchanged. Acutely, betamethasone did not affect SEP latencies and amplitudes 4 and 24 h following administration. Chronically, betamethasone delayed developmental decrease in the N200 but not N20 latency by 2 weeks without affecting amplitudes. In parallel, betamethasone decreased subcortical white matter myelination but did not affect network formation and synaptic density in the somatosensory cortex. CONCLUSION: Somatosensory stimuli are already processed by the foetal cerebral cortex at the beginning of the third trimester. Subsequent developmental decrease in SEP latencies suggests ongoing maturation of afferent sensory transmission. Antenatal glucocorticoids affect structural and functional development of the somatosensory system with specific effects at subcortical level.

Perceived cognitive impairments after critical illness: a longitudinal study in survivors and family member controls.

BACKGROUND: Many former intensive care unit (ICU) patients report difficulties in cognitive functions especially in their daily life. We aimed to measure perceived cognitive impairments in daily life in survivors of critical illness and their family member controls (FMC). METHODS: Perceived cognitive impairments were assessed two times after ICU discharge using an adapted German version of the "Functional Assessment of Cancer Therapy - Cognitive Function" questionnaire. After 3 months, 127 former patients and 52 FMC participated and 103/127 patients and 36/52 FMC were followed up after 6 months. Baseline information was obtained retrospectively. RESULTS: We found no significant differences between the patient sample and FMC, 3 and 6 months after ICU discharge. Based on questionnaire ratings, cluster analysis divided patients and FMC into a cognitively 'impaired' and a 'non-impaired' cluster. Questionnaire scales differed significantly prior to ICU admission as well as 3 and 6 months after ICU discharge between both clusters. While differences between patients and FMC were less pronounced in the 'non-impaired' cluster, patients were significantly more impaired than FMC at 3 and 6 months after ICU discharge in the 'impaired' cluster. DISCUSSION: A substantial part of former patients were affected by post-ICU cognitive impairment in daily life. Pre-existing cognitive impairments were a risk factor. These patients would probably profit from tailored neurorehabilitative therapy. Therefore, an efficient tool to identify potential patients for neurorehabilitation is needed. The questionnaire revealed good psychometric properties. We recommend a comprehensive validation of the questionnaire in this patient population.

Advances in PET Detection of the Antitumor T Cell Response.

Positron emission tomography (PET) is a powerful noninvasive imaging technique able to measure distinct biological processes in vivo by administration of a radiolabeled probe. Whole-body measurements track the probe accumulation providing a means to measure biological changes such as metabolism, cell location, or tumor burden. PET can also be applied to both preclinical and clinical studies providing three-dimensional information. For immunotherapies (in particular understanding T cell responses), PET can be utilized for spatial and longitudinal tracking of T lymphocytes. Although PET has been utilized clinically for over 30 years, the recent development of additional PET radiotracers have dramatically expanded the use of PET to detect endogenous or adoptively transferred T cells in vivo. Novel probes have identified changes in T cell quantity, location, and function. This has enabled investigators to track T cells outside of the circulation and in hematopoietic organs such as spleen, lymph nodes, and bone marrow, or within tumors. In this review, we cover advances in PET detection of the antitumor T cell response and areas of focus for future studies.

Assessment of fetal maturation age by heart rate variability measures using random forest methodology.

Fetal maturation age assessment based on heart rate variability (HRV) is a predestinated tool in prenatal diagnosis. To date, almost linear maturation characteristic curves are used in univariate and multivariate models. Models using complex multivariate maturation characteristic curves are pending. To address this problem, we use Random Forest (RF) to assess fetal maturation age and compare RF with linear, multivariate age regression. We include previously developed HRV indices such as traditional time and frequency domain indices and complexity indices of multiple scales. We found that fetal maturation was best assessed by complexity indices of short scales and skewness in state-dependent datasets (quiet sleep, active sleep) as well as in state-independent recordings. Additionally, increasing fluctuation amplitude contributed to the model in the active sleep state. None of the traditional linear HRV parameters contributed to the RF models. Compared to linear, multivariate regression, the mean prediction of gestational age (GA) is more accurate with RF than in linear, multivariate regression (quiet state: R(2)=0,617 vs. R(2)=0,461, active state: R(2)=0,521 vs. R(2)=0,436, state independent: R(2)=0,583 vs. R(2)=0,548). We conclude that classification and regression tree models such as RF methodology are appropriate for the evaluation of fetal maturation age. The decisive role of adjustments between different time scales of complexity may essentially extend previous analysis concepts mainly based on rhythms and univariate complexity indices. Those system characteristics may have implication for better understanding and accessibility of the maturating complex autonomic control and its disturbance.

Dysautonomia in prodromal α-synucleinopathy: peripheral versus central autonomic degeneration.

BACKGROUND AND PURPOSE: There is an urgent need for early predictive markers for the course of disease in prodromal α-synucleinopathies such as idiopathic rapid eye movement (REM) sleep behaviour disorder. Autonomic cardiac/vascular dysfunction is a prominent feature in advanced α-synucleinopathies, but its diagnostic value as an early neurodegenerative marker remains unclear. The latter may be complicated since synuclein-mediated neurodegeneration may involve central and peripheral components of the autonomic nervous system. METHODS: The diagnostic value of autonomic symptoms and central and peripheral autonomic markers of blood pressure and heart rate regulation were prospectively evaluated in 20 subjects with idiopathic REM sleep behaviour disorder and 20 age-matched healthy controls. RESULTS: Although subjects with REM sleep behaviour disorder showed no clinical autonomic symptoms, blood pressure (P ≤ 0.035) and heart rate response (P ≤ 0.065) were slightly diminished during orthostatic challenge. Autonomic dysregulation was distinctively reflected in lower resting heart rate (all components, P ≤ 0.05) and blood pressure variability (low frequency component, P ≤ 0.024) indicating peripheral cardiac/vascular denervation. In contrast, baroreflex sensitivity and central cardiac autonomic outflow (sympathovagal balance) were well preserved indicating intact central autonomic regulation. Heart rate variability [very low frequency component, receiver operating characteristic (ROC) area under the curve (AUC) 0.80, P ≤ 0.001] and blood pressure variability (low frequency component ROC AUC 0.73, P ≤ 0.01) but not baroreflex sensitivity and sympathovagal balance showed an excellent diagnostic accuracy in identifying subjects with REM sleep behaviour disorder and healthy controls. CONCLUSIONS: Cardiac/vascular dysfunction in prodromal α-synucleinopathy arises from peripheral rather than from central autonomic degeneration. Autonomic indices encoded in heart rate and blood pressure variability are precise functional markers of early synuclein-mediated neurodegeneration.

Consistent and reproducible staining of glia by a modified Golgi-Cox method.

BACKGROUND: Golgi-Cox staining is a powerful histochemical approach which has been used extensively to visualize the morphology of neurons and glia. However, its usage as a first-choice method is hindered by its uncertain nature, diminished consistency and lengthy staining duration. The FD Rapid GolgiStain™ Kit (FD Neurotechnologies, Inc., USA) has been developed by employing the Golgi-Cox approach. It is a simple, reliable and reproducible way of performing Golgi impregnation for the analysis of neuronal morphology. NEW METHOD: We report here simple modifications to the manufacturer's protocol which enable reproducible and reliable staining of glial cells. RESULTS: Exposure of brain tissue to 4% paraformaldehyde (PFA) during perfusion followed by postfixation with 8% glutaraldehyde in 4% PFA led to only glial cells being stained, whereas in the absence of postfixation both neurons and glia were stained with unclear morphology. Additionally, we found that impregnation at 26°C±1 was critical to attain uniform staining. COMPARISON WITH EXISTING METHOD: Our modified Golgi-Cox approach is consistent and reproducible and affords uniform glial staining throughout the brain. CONCLUSION: As this protocol stains only a small percentage of cells, it is suitable for the analysis of individual cells.

Primary somatosensory contextual modulation is encoded by oscillation frequency change.

OBJECTIVE: This study characterized thalamo-cortical communication by assessing the effect of context-dependent modulation on the very early somatosensory evoked high-frequency oscillations (HF oscillations). METHODS: We applied electrical stimuli to the median nerve together with an auditory oddball paradigm, presenting standard and deviant target tones representing differential cognitive contexts to the constantly repeated electrical stimulation. Median nerve stimulation without auditory stimulation served as unimodal control. RESULTS: A model consisting of one subcortical (near thalamus) and two cortical (Brodmann areas 1 and 3b) dipolar sources explained the measured HF oscillations. Both at subcortical and the cortical levels HF oscillations were significantly smaller during bimodal (somatosensory plus auditory) than unimodal (somatosensory only) stimulation. A delay differential equation model was developed to investigate interactions within the 3-node thalamo-cortical network. Importantly, a significant change in the eigenfrequency of Brodmann area 3b was related to the context-dependent modulation, while there was no change in the network coupling. CONCLUSION: This model strongly suggests cortico-thalamic feedback from both cortical Brodmann areas 1 and 3b to the thalamus. With the 3-node network model, thalamo-cortical feedback could be described. SIGNIFICANCE: Frequency encoding plays an important role in contextual modulation in the somatosensory thalamo-cortical network.

Muscle ultrasonography as an additional diagnostic tool for the diagnosis of amyotrophic lateral sclerosis.

OBJECTIVE: We aimed to determine the utility of muscle ultrasonography (MUS) in addition to electromyography (EMG) in the diagnosis of amyotrophic lateral sclerosis (ALS). METHODS: In all, 60 patients with ALS and 20 with other neuromuscular disorders underwent MUS and EMG. In addition, 30 healthy controls underwent only MUS. Occurrence of fasciculations and fibrillations was evaluated. Ultrasonic echogenicity was graded semiquantitatively. RESULTS: The incidence of fasciculations was significantly higher in patients undergoing MUS than in those undergoing EMG (p<0.05), even in muscles of full strength (p<0.001). However, EMG was more sensitive in detecting fibrillations (p<0.05). MUS had an overall higher sensitivity in detecting spontaneous activity in the tongue (p<0.05). Patients with ALS showed significantly increased muscle echo intensity (EI) compared to patients who were initially suspected as having ALS and normal controls (p<0.05), irrespective of the clinical or electrophysiological status. CONCLUSION: Our results showed that the sensitivity and specificity of MUS in diagnosing ALS was almost equivalent to those of EMG, using the Awaji criteria. Combination of MUS and EMG enhances the diagnostic accuracy compared to EMG alone (p<0.05). SIGNIFICANCE: The combination of EMG and MUS can be used to evaluate the lower motor neuron affection by reducing the use of the often painful and uncomfortable EMG examinations but without decreasing the diagnostic sensitivity and specificity.

[Supraorbital approach to treat a fronto-orbital fracture with pneumocephaly, a minimal invasive technique]. / Abord supraorbitaire pour traiter une fracture frontale avec pneumocéphalie, une technique peu invasive.

We describe a supraorbital approach through an upper eyebrow skin incision to treat a fronto-orbital fracture with pneumocephaly in a 84-year-old cardiac patient. The clinical and cosmetic results are excellent. This case is illustrated by pre- and postoperative CT-scan and MRI as well as pictures showing the minimal invasive technique.

Developing fetal motor-cardiovascular coordination analyzed from multi-channel magnetocardiography.

Fetal movements (FM) related heart rate accelerations (AC) are an important maturation criterion. Since Doppler-based time resolution is not sufficient for accompanying heart rate variability analysis, the work is aimed at a comprehensive FM-AC analysis using magnetocardiographic recordings from fetuses during sleep.We identify FM and AC by independent component analysis and automatic recognition algorithms. We investigate associations between FM and AC of different magnitude by means of event coincidence and time series cross-correlation over the maturation period of 21-40 weeks of gestation (WGA).FM related AC appear with increasing AC magnitude and WGA. Vice versa, AC related FM appear independent of WGA, but more frequently with increasing AC amplitude. The FM-AC correlation exists already at 21 WGA and further increases with WGA while the variability of its time delay decreases. Hence, FM and AC are clearly associated over the whole investigated maturation period. The increase of FM related AC runs parallel to the increasing AC magnitude.The MCG methodology was confirmed and results from previous Doppler-based analyses reproduced. Hence, MCG recordings allow the collective analysis of heart rate variability based maturation indices and FM related AC. This synergism may improve the diagnosis of fetal developmental disorders.

Endoplasmic reticulum stress is accompanied by activation of NF-κB in amyotrophic lateral sclerosis.

BACKGROUND: Recent studies have indicated that endoplasmic reticulum (ER) stress is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). ER stress occurs when the ER-mitochondria calcium cycle is disturbed and misfolded proteins accumulate in the ER. To cope with ER stress, cells activate the unfolded protein response (UPR). Accumulating evidence from non-neuronal cell models suggests that there is extensive cross-talk between the UPR and the NF-κB pathway. METHODS: Here we investigated the expression of NF-κB and the main UPR markers X-box binding protein 1 (XBP1), basic leucine-zipper transcription factor 6 (ATF6) and phosphorylated eukaryotic initiation factor-2α (p-eIF2) in mutated SOD1(G93A) cell models of ALS, as well as their modulation by lipopolysaccharide and ER-stressing (tunicamycin) stimuli. RESULTS: Expression of NF-κB was enhanced in the presence of SOD1(G93A). Lipopolysaccharide did not induce the UPR in NSC34 cells and motor neurons in a mixed motor neuron-glia coculture system. The induction of the UPR by tunicamycin was accompanied by activation of NF-κB in NSC34 cells and motor neurons. CONCLUSION: Our data linked two important pathogenic mechanisms of ALS, ER stress and NF-κB signalling, in motor neurons.