The Regulation of Fatty Acid Synthase by Exosomal miR-143-5p and miR-342-5p in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease caused by an aberrant repair of injured alveolar epithelial cells. The maintenance of the alveolar epithelium and its regeneration after the damage is fueled by alveolar type II (ATII) cells. Injured cells release exosomes containing microRNAs (miRNAs), which can alter the recipient cells' function. Lung tissue, ATII cells, fibroblasts, plasma, and exosomes were obtained from naive patients with IPF, patients with IPF taking pirfenidone or nintedanib, and control organ donors. miRNA expression was analyzed to study their impact on exosome-mediated effects in IPF. High miR-143-5p and miR-342-5p levels were detected in ATII cells, lung tissue, plasma, and exosomes in naive patients with IPF. Decreased FASN (fatty acid synthase) and ACSL-4 (acyl-CoA-synthetase long-chain family member 4) expression was found in ATII cells. miR-143-5p and miR-342-5p overexpression or ATII cell treatment with IPF-derived exosomes containing these miRNAs lowered FASN and ACSL-4 levels. Also, this contributed to ATII cell injury and senescence. However, exosomes isolated from patients with IPF taking nintedanib or pirfenidone increased FASN expression in ATII cells compared with naive patients with IPF. Furthermore, fibroblast treatment with exosomes obtained from naive patients with IPF increased SMAD3, CTGF, COL3A1, and TGFß1 expression. Our results suggest that IPF-derived exosomes containing miR-143-5p and miR-342-5p inhibited the de novo fatty acid synthesis pathway in ATII cells. They also induced the profibrotic response in fibroblasts. Pirfenidone and nintedanib improved ATII cell function and inhibited fibrogenesis. This study highlights the importance of exosomes in IPF pathophysiology.

Central vestibular networking for sensorimotor control, cognition, and emotion.

PURPOSE OF REVIEW: The aim of this study was to illuminate the extent of the bilateral central vestibular network from brainstem and cerebellum to subcortical and cortical areas and its interrelation to higher cortical functions such as spatial cognition and anxiety. RECENT FINDINGS: The conventional view that the main function of the vestibular system is the perception of self-motion and body orientation in space and the sensorimotor control of gaze and posture had to be developed further by a hierarchical organisation with bottom-up and top-down interconnections. Even the vestibulo-ocular and vestibulo-spinal reflexes are modified by perceptual cortical processes, assigned to higher vestibulo-cortical functions. A first comparative fMRI meta-analysis of vestibular stimulation and fear-conditioning studies in healthy participants disclosed widely distributed clusters of concordance, including the prefrontal cortex, anterior insula, temporal and inferior parietal lobe, thalamus, brainstem and cerebellum. In contrast, the cortical vestibular core region around the posterior insula was activated during vestibular stimulation but deactivated during fear conditioning. In recent years, there has been increasing evidence from studies in animals and humans that the central vestibular system has numerous connections related to spatial sensorimotor performance, memory, and emotion. The clinical implication of the complex interaction within various networks makes it difficult to assign some higher multisensory disorders to one particular modality, for example in spatial hemineglect or room-tilt illusion. SUMMARY: Our understanding of higher cortical vestibular functions is still in its infancy. Different brain imaging techniques in animals and humans are one of the most promising methodological approaches for further structural and functional decoding of the vestibular and other intimately interconnected networks. The multisensory networking including cognition and emotion determines human behaviour in space.

Multimodal Mobility Assessment Predicts Fall Frequency and Severity in Cerebellar Ataxia.

This cohort study aims to evaluate the predictive validity of multimodal clinical assessment and quantitative measures of in- and off-laboratory mobility for fall-risk estimation in patients with cerebellar ataxia (CA).Occurrence, severity, and consequences of falling were prospectively assessed for 6 months in 93 patients with hereditary (N = 36) and sporadic or secondary (N = 57) forms of CA and 63 healthy controls. Participants completed a multimodal clinical and functional fall risk assessment, in-laboratory gait examination, and a 2-week inertial sensor-based daily mobility monitoring. Multivariate logistic regression analyses were performed to evaluate the predictive capacity of all clinical and in- and off-laboratory mobility measures with respect to fall (1) status (non-faller vs. faller), (2) frequency (occasional vs. frequent falls), and (3) severity (benign vs. injurious fall) of patients. 64% of patients experienced one or recurrent falls and 65% of these severe fall-related injuries during prospective assessment. Mobility impairments in patients corresponded to a mild-to-moderate ataxic gait disorder. Patients' fall status and frequency could be reliably predicted (78% and 81% accuracy, respectively), primarily based on their retrospective fall status. Clinical scoring of ataxic symptoms and in- and off-laboratory gait and mobility measures improved classification and provided unique information for the prediction of fall severity (84% accuracy).These results encourage a stepwise approach for fall risk assessment in patients with CA: fall history-taking readily and reliably informs the clinician about patients' general fall risk. Clinical scoring and instrument-based mobility measures provide further in-depth information on the risk of recurrent and injurious falling.

Physiological oculo-auricular-facial-mandibular synkinesis elicited in humans by gaze deviations.

Integrated motor behaviors involving ocular motion-associated movements of the head, neck, pinna, and parts of the face are commonly seen in animals orienting to a visual target. A number of coordinated movements have also been observed in humans making rapid gaze shifts to horizontal extremes, which may be vestiges of these. Since such integrated mechanisms point to a nonpathological coactivation of several anatomically separate cranial circuits in humans, it is important to see how the different pairs of integrative motor behaviors with a common trigger (i.e., ocular motion) manifest in relation to one another. Here, we systematically examined the pattern of eye movement-induced recruitment of multiple cranial muscles in humans. Simultaneous video-oculography and bilateral surface electromyograms of transverse auricular, temporalis, frontalis, and masseter muscles were recorded in 15 healthy subjects (8 females; 29.3 ± 5.2 yr) while they made head-fixed, horizontal saccadic, pursuit, and optokinetic eye movements. Potential chin laterotrusion linked to contractions of masticator muscles was captured with a jaw-fixed accelerometer. Our findings objectively show an orchestrated aural-facial-masticatory muscle response to a range of horizontal eye movements (prevalence of 21%-93%). These responses were most prominent during eccentric saccades. We further reveal distinctions between the various observed activation patterns in terms of their profile (transient or sustained), laterality (with respect to direction of gaze), and timing (with respect to saccade onset). Possible underlying neural substrates, their atavistic behavioral significance, and potential clinical applications for monitoring sensory attention and designing attention-directed hearing aids in the future are discussed.NEW & NOTEWORTHY Healthy humans exhibit different combinations of nonpathological, synkinetic gaze-associated movements with aural, facial, and/or masticatory muscles during different types of voluntary and reflexive horizontal eye movements. The manifestations of these collective phenomena are strongest during large-scale horizontal saccades and accompanied by a detectable horizontal chin movement. Auricular muscle activations occur equally on both sides, whereas the activation of facial and masticatory muscles is predominantly ipsilateral (in regard to gaze direction).

Validation of a comprehensive diagnostic algorithm for patients with acute vertigo and dizziness.

BACKGROUND AND PURPOSE: Vertigo and dizziness are common complaints in emergency departments and primary care, and pose major diagnostic challenges due to their various underlying etiologies. Most supportive diagnostic algorithms concentrate on either identifying cerebrovascular events (CVEs) or diagnosing specific vestibular disorders or are restricted to specific patient subgroups. The aim of the present study was to develop and validate a comprehenisve algorithm for identifying patients with CVE and classifying the most common vestibular disorders. METHODS: The study was conducted within the scope of the "PoiSe" project (Prevention, Online feedback, and Interdisciplinary Therapy of Acute Vestibular Syndromes by e-health). A three-level algorithm was developed according to international guidelines and scientific evidence, addressing both the detection of CVEs and the classification of non-vascular vestibular disorders (unilateral vestibulopathy, benign paroxysmal positional vertigo, vestibular paroxysmia, Menière's disease, vestibular migraine, functional dizziness). The algorithm was validated in a prospectively collected dataset of 407 patients with acute vertigo and dizziness presenting to the Emergency Department at the Ludwig-Maximilian University of Munich. RESULTS: The algorithm assigned 287 of 407 patients to the correct diagnosis, corresponding to an overall accuracy of 71%. CVEs were identified with high sensitivity of 94%. The six most common vestibular disorders were classified with high specificity, above 95%. Random forest identified presence of a paresis, sensory loss, central ocular motor and vestibular signs (HINTS [head impulse test, nystagmus assessment, and test of skew deviation]), and older age as the most important variables indicating a cerebrovascular event. CONCLUSIONS: The proposed diagnostic algorithm can correctly classify the most common vestibular disorders based on a comprehensive set of key questions and clinical examinations. It is easily applied, not limited to subgroups, and might therefore be transferred to broad clinical settings such as primary healthcare.

Dynamic whole-brain metabolic connectivity during vestibular compensation in the rat.

Unilateral damage to the inner ear results in an acute vestibular syndrome, which is compensated within days to weeks due to adaptive cerebral plasticity. This process, called central vestibular compensation (VC), involves a wide range of functional and structural mechanisms at the cellular and network level. The short-term dynamics of whole-brain functional network recruitment and recalibration during VC has not been depicted in vivo. The purpose of this study was to investigate the interplay of separate and distinct brain regions and in vivo networks in the course of VC by sequential [18F]-FDG-PET-based statistical and graph theoretical analysis with the aim of revealing the metabolic connectome before and 1, 3, 7, and 15 days post unilateral labyrinthectomy (UL) in the rat. Temporal changes in metabolic brain connectivity were determined by Pearson's correlation (|r| > 0.5, p < 0.001) of regional cerebral glucose metabolism (rCGM) in 57 segmented brain regions. Metabolic connectivity analysis was compared to univariate voxel-wise statistical analysis of rCGM over time and to behavioral scores of static and dynamic sensorimotor recovery. Univariate statistical analysis revealed an ipsilesional relative rCGM decrease (compared to baseline) and a contralesional rCGM increase in vestibular and limbic networks and an increase in bilateral cerebellar and sensorimotor networks. Quantitative analysis of the metabolic connections showed a maximal increase from baseline to day 3 post UL (interhemispheric: 2-fold, ipsilesional: 3-fold, contralesional: 12-fold) and a gradual decline until day 15 post UL, which paralleled the dynamics of vestibular symptoms. In graph theoretical analysis, an increase in connectivity occurred especially within brain regions associated with brainstem-cerebellar and thalamocortical vestibular networks and cortical sensorimotor networks. At the symptom peak (day 3 post UL), brain networks were found to be organized in large ensembles of distinct and highly connected hubs of brain regions, which separated again with progressing VC. Thus, we found rapid changes in network organization at the subcortical and cortical level and in both hemispheres, which may indicate an initial functional substitution of vestibular loss and subsequent recalibration and reorganization of sensorimotor networks during VC.

Early uneven ear input induces long-lasting differences in left-right motor function.

How asymmetries in motor behavior become established normally or atypically in mammals remains unclear. An established model for motor asymmetry that is conserved across mammals can be obtained by experimentally inducing asymmetric striatal dopamine activity. However, the factors that can cause motor asymmetries in the absence of experimental manipulations to the brain remain unknown. Here, we show that mice with inner ear dysfunction display a robust left or right rotational preference, and this motor preference reflects an atypical asymmetry in cortico-striatal neurotransmission. By unilaterally targeting striatal activity with an antagonist of extracellular signal-regulated kinase (ERK), a downstream integrator of striatal neurotransmitter signaling, we can reverse or exaggerate rotational preference in these mice. By surgically biasing vestibular failure to one ear, we can dictate the direction of motor preference, illustrating the influence of uneven vestibular failure in establishing the outward asymmetries in motor preference. The inner ear-induced striatal asymmetries identified here intersect with non-ear-induced asymmetries previously linked to lateralized motor behavior across species and suggest that aspects of left-right brain function in mammals can be ontogenetically influenced by inner ear input. Consistent with inner ear input contributing to motor asymmetry, we also show that, in humans with normal ear function, the motor-dominant hemisphere, measured as handedness, is ipsilateral to the ear with weaker vestibular input.

'Excess anxiety' and 'less anxiety': both depend on vestibular function.

PURPOSE OF REVIEW: To present evidence of a functional interrelation between the vestibular and the anxiety systems based on a complex reciprocally organized network. The review focuses on the differential effects of various vestibular disorders, on psychiatric comorbidity, and on anxiety related to vertigo. RECENT FINDINGS: Episodic vertigo syndromes such as vestibular migraine, vestibular paroxysmia, and Menière's disease are associated with a significant increase of psychiatric comorbidity, in particular anxiety/phobic disorders and depression. Chronic unilateral and bilateral vestibulopathy (BVP) do not exhibit a higher than normal psychiatric comorbidity. Anxiety related to the vertigo symptoms is also increased in episodic structural vestibular disorders but not in patients with chronic unilateral or bilateral loss of vestibular function. The lack of vertigo-related anxiety in BVP is a novel finding. Several studies have revealed special features related to anxiety in patients suffering from BVP: despite objectively impaired postural balance with frequent falls, they usually do not complain about fear of falling; they do not report an increased susceptibility to fear of heights; they do not have an increased psychiatric comorbidity; and they do not report increased anxiety related to the perceived vertigo. Subtle or moderate vestibular stimulation (by galvanic currents or use of a swing) may have beneficial effects on stress or mood state in healthy adults, and promote sleep in humans and rodents. The intimate structural and functional linkage of the vestibular and anxiety systems includes numerous nuclei, provincial and connector hubs, the thalamocortical network, and the cerebellum with many neural transmitter systems. SUMMARY: The different involvement of emotional processes and anxiety - to the extent of 'excess anxiety' or 'less anxiety' - in structural vestibular disorders may be due to the specific dysfunction and whether the system activity is excited or diminished. Both psychiatric comorbidity and vertigo-related anxiety are maximal with excitation and minimal with loss of peripheral vestibular function.

Thalamocortical network: a core structure for integrative multimodal vestibular functions.

PURPOSE OF REVIEW: To apply the concept of nonreflexive sensorimotor and cognitive vestibular functions and disturbances to the current view of separate right and left thalamocortical systems. RECENT FINDINGS: The neuronal modules for sensorimotor and cognitive functions are organized in so-called provincial hubs with intracommunity connections that interact task-dependently via connector hubs. Thalamic subnuclei may serve not only as provincial hubs but also in higher order nuclei as connector hubs. Thus, in addition to its function as a cortical relay station of sensory input, the human thalamus can be seen as an integrative hub for brain networks of higher multisensory vestibular function. Imaging studies on the functional connectivity have revealed a dominance of the right side in right-handers at the upper brainstem and thalamus. A connectivity-based parcellation study has confirmed the asymmetrical organization (i.e., cortical dominance) of the parieto-insular vestibular cortex, an area surrounded by other vestibular cortical areas with symmetrical (nondominant) organization. Notably, imaging techniques have shown that there are no crossings of the vestibular pathways in between the thalamic nuclei complexes. Central vestibular syndromes caused by lesions within the thalamocortical network rarely manifest with rotational vertigo. This can be explained and mathematically simulated by the specific coding of unilateral vestibular dysfunction within different cell systems, the angular velocity cell system (rotational vertigo in lower brainstem lesions) in contrast to the head direction cell system (directional disorientation and swaying vertigo in thalamocortical lesions). SUMMARY: The structural and functional separation of the two thalamic nuclei complexes allowed a lateralization of the right and left hemispheric functions to develop. Furthermore, it made possible the simultaneous performance of sensorimotor and cognitive tasks, which require different spatial reference systems in opposite hemispheres, for example, egocentric manipulation of objects (handedness) and allocentric orientation of the self in the environment by the multisensory vestibular system.

[Vertigo, a Driver's Licence with and without Permission to Drive: Are the Current Guidelines Justified?] / Schwindel, von der Fahreignung mit Führerschein zum Führerschein ohne Fahreignung: Sind die aktuellen Leitlinien gerechtfertigt?

This article critically discusses the current assessment guidelines valid since 2014 which must be applied to determine the driving aptitude of patients with dizziness and balance disorders (in the official document called "disorders of the sense of balance"). With all due respect for the meticulous work of the expert commission who established the guidelines - the likes of which are not known anywhere else - we consider their revision imperative. On the basis of our many years of experience in the German Center for Dizziness and Balance Disorders of the LMU Munich it is our opinion that these restrictions are too strict and the required dizziness-free intervals are too long.The guidelines now stipulate the following for drivers with a group 1 driving licence ("private"):1) Patients with Meniere's disease (attacks without prodromes) must have had no attacks for 2 years before it is possible to drive a car again.2) Patients with vestibular migraine without prodromes must not have had any attacks for 3 years.The following stipulations hold for drivers with a group 1 and group 2 driving licence ("professional driver"):3) Patients with bilateral vestibulopathy as a rule are considered to have a driving disability, likewise4) Patients with central vestibular forms of vertigo, e. g., oculomotor disorders like downbeat and upbeat nystagmus syndromes are also as a rule regarded as having a driving disability.5) Patients with functional (psychogenic) forms of dizziness (e. g., phobic postural vertigo) who have a group 1 driving licence are considered to have a driving disability if dizziness occurs while driving. Those with a group 2 driving licence are in general considered to have a driving disability. However, many patients with episodic or chronic dizziness have such minor symptoms that their driving fitness is not relevantly impaired or if they do have an attack, they are able to stop driving in a controlled manner. In contrast, the restrictions on other illnesses that are accompanied by attack-like disorders of cognition and consciousness like the epilepsies are less strict. Depending on the type of attack or its trigger, the attack-free interval for such patients with a group 1 driving licence amounts to 3 months up to 1 year, although they clearly are not fit to drive during an attack.

Global orientation in space and the lateralization of brain functions.

PURPOSE OF REVIEW: The functional role of the vestibular system for multisensory orientation and sensorimotor control is reviewed with a special focus on hemispherical lateralization and its consequences for neurological disorders of higher cortical function. RECENT FINDINGS: The peripheral and central vestibular systems are bilaterally organized with ipsilateral and contralateral ascending pathways and two multisensory cortical networks in the right and left hemisphere. The vestibular cortical system shows a structural and functional lateralization with a dominance of the right hemisphere in right-handers and the left hemisphere in left-handers. Although the vestibular brainstem pathways are evenly distributed at lower pontine level, an increasing lateralization builds up because of an asymmetric number of pontine and mesencephalic crossing fibers from left to right in right-handers. This vestibular lateralization causes more frequent and more severe disorders of higher sensorimotor dysfunction in lesions of the right hemisphere such as in hemispatial neglect and the pusher syndrome. SUMMARY: There is evidence that multisensory higher vestibular functions including large-scale spatial orientation, spatial memory and navigation are dominated by the right temporo-parietal cortex. A beneficial result of lateralization of brain functions in healthy individuals is that it enables the individual to produce a global sensorimotor response even in case of a mismatch of the actual right and left sensory inputs. The consequence for neurology, however, is that lesions in the dominant hemisphere cause more frequently and more severe disorders such as the visuo-spatial hemineglect and the pusher syndrome.

Differential Involvement during Latent Herpes Simplex Virus 1 Infection of the Superior and Inferior Divisions of the Vestibular Ganglia: Implications for Vestibular Neuritis.

Controversy still surrounds both the etiology and pathophysiology of vestibular neuritis (VN). Especially uncertain is why the superior vestibular nerve (SVN) is more frequently affected than the inferior vestibular nerve (IVN), which is partially or totally spared. To address this question, we developed an improved method for preparing human vestibular ganglia (VG) and nerve. Subsequently, macro- and microanatomical as well as PCR studies were performed on 38 human ganglia from 38 individuals. The SVN was 2.4 mm longer than the IVN, and in 65% of the cases, the IVN ran in two separate bony canals, which was not the case for the SVN. Anastomoses between the facial and cochlear nerves were more common for the SVN (14/38 and 9/38, respectively) than for the IVN (7/38 and 2/38, respectively). Using reverse transcription-quantitative PCR (RT-qPCR), we found only a few latently herpes simplex virus 1 (HSV-1)-infected VG (18.4%). In cases of two separate neuronal fields, infected neurons were located in the superior part only. In summary, these PCR and micro- and macroanatomical studies provide possible explanations for the high frequency of SVN infection in vestibular neuritis.IMPORTANCE Vestibular neuritis is known to affect the superior part of the vestibular nerve more frequently than the inferior part. The reason for this clinical phenomenon remains unclear. Anatomical differences may play a role, or if latent HSV-1 infection is assumed, the etiology may be due to the different distribution of the infection. To shed further light on this subject, we conducted different macro- and microanatomical studies. We also assessed the presence of HSV-1 in VG and in different sections of the VG. Our findings add new information on the macro- and microanatomy of the VG as well as the pathophysiology of vestibular neuritis. We also show that latent HSV-1 infection of VG neurons is less frequent than previously reported.

Pathological ponto-cerebello-thalamo-cortical activations in primary orthostatic tremor during lying and stance.

Primary orthostatic tremor is a rare neurological disease characterized mainly by a high frequency tremor of the legs while standing. The aim of this study was to identify the common core structures of the oscillatory circuit in orthostatic tremor and how it is modulated by changes of body position. Ten patients with orthostatic tremor and 10 healthy age-matched control subjects underwent a standardized neurological and neuro-ophthalmological examination including electromyographic and posturographic recordings. Task-dependent changes of cerebral glucose metabolism during lying and standing were measured in all subjects by sequential 18F-fluorodeoxyglucose-positron emission tomography on separate days. Results were compared between groups and conditions. All the orthostatic tremor patients, but no control subject, showed the characteristic 13-18 Hz tremor in coherent muscles during standing, which ceased in the supine position. While lying, patients had a significantly increased regional cerebral glucose metabolism in the pontine tegmentum, the posterior cerebellum (including the dentate nuclei), the ventral intermediate and ventral posterolateral nucleus of the thalamus, and the primary motor cortex bilaterally compared to controls. Similar glucose metabolism changes occurred with clinical manifestation of the tremor during standing. The glucose metabolism was relatively decreased in mesiofrontal cortical areas (i.e. the medial prefrontal cortex, supplementary motor area and anterior cingulate cortex) and the bilateral anterior insula in orthostatic tremor patients while lying and standing. The mesiofrontal hypometabolism correlated with increased body sway in posturography. This study confirms and further elucidates ponto-cerebello-thalamo-primary motor cortical activations underlying primary orthostatic tremor, which presented consistently in a group of patients. Compared to other tremor disorders one characteristic feature in orthostatic tremor seems to be the involvement of the pontine tegmentum in the pathophysiology of tremor generation. High frequency oscillatory properties of pontine tegmental neurons have been reported in pathological oscillatory eye movements. It is remarkable that the characteristic activation and deactivation pattern in orthostatic tremor is already present in the supine position without tremor presentation. Multilevel changes of neuronal excitability during upright stance may trigger activation of the orthostatic tremor network. Based on the functional imaging data described in this study, it is hypothesized that a mesiofrontal deactivation is another characteristic feature of orthostatic tremor and plays a pivotal role in development of postural unsteadiness during prolonged standing.

Strain-Release Heteroatom Functionalization: Development, Scope, and Stereospecificity.

Driven by the ever-increasing pace of drug discovery and the need to push the boundaries of unexplored chemical space, medicinal chemists are routinely turning to unusual strained bioisosteres such as bicyclo[1.1.1]pentane, azetidine, and cyclobutane to modify their lead compounds. Too often, however, the difficulty of installing these fragments surpasses the challenges posed even by the construction of the parent drug scaffold. This full account describes the development and application of a general strategy where spring-loaded, strained C-C and C-N bonds react with amines to allow for the "any-stage" installation of small, strained ring systems. In addition to the functionalization of small building blocks and late-stage intermediates, the methodology has been applied to bioconjugation and peptide labeling. For the first time, the stereospecific strain-release "cyclopentylation" of amines, alcohols, thiols, carboxylic acids, and other heteroatoms is introduced. This report describes the development, synthesis, scope of reaction, bioconjugation, and synthetic comparisons of four new chiral "cyclopentylation" reagents.

3-D spatial memory and navigation: functions and disorders.

PURPOSE OF REVIEW: The aim of this review is to report on the specialized neuronal systems mediating spatial orientation and navigation discovered in animal experiments. These findings have important implications for the clinical management of patients with vestibular disorders or dementia and for translational research in these fields. RECENT FINDINGS: The following anatomically and functionally separate, but nevertheless cooperative cell types have been characterized: angular head velocity cells and head direction cells, which depend on vestibular input and interact with place cells and grid cells, which represent position and distance. The entire system is thought to encode internal cognitive maps whose spatial data can be utilized for navigation and orientation. Flying and swimming species use spatial orientation and navigation isotropically, i.e., in the earth-horizontal and vertical directions, whereas ground-based species, including humans, perform better in the earth-horizontal plane (anisotropically). Examples of clinical disorders with deficits of spatial orientation and navigation are bilateral peripheral vestibulopathy, mild cognitive impairment, and dementia. SUMMARY: Testing spatial orientation and navigation should become an integral part of routine neurological examinations, especially in the elderly. Also desirable are the further development and standardization of simple and reliable smart phone-based bedside tests to measure these functions in patients.

Descriptions of vestibular migraine and Menière's disease in Greek and Chinese antiquity.

Background Vestibular migraine and Menière's disease are two types of episodic vertigo syndromes that were already observed in Greek and Chinese antiquity. Descriptions first appeared in the work of the classical Greek physician Aretaeus of Cappadocia, who lived in the 2nd century AD, and in Huangdi Neijing, a seminal medical source in the Chinese Medical Classics, written between the 2nd century BC and the 2nd century AD. Aim The aim of this paper is to search in Aretaeus' book De causis et signis acutorum et chronicorum morborum and in Huangdi Neijing for descriptions of vertigo co-occurring with headache or ear symptoms that resemble current classifications of vestibular migraine or Menière's disease. Results Aretaeus describes a syndrome combining headache, vertigo, visual disturbance, oculomotor phenomena, and nausea that resembles the symptoms of vestibular migraine. In the Chinese book Huangdi Neijing the Yellow Thearch mentions the co-occurrence of episodic dizziness and a ringing noise of the ears that recalls an attack of Menière's disease. Conclusions The descriptions of these two conditions in Greek and Chinese antiquity are similar to the vertigo syndromes currently classified as vestibular migraine and Menière's disease. In clinical practice it may be difficult to clearly differentiate between them, and they may also co-occur.

Anisotropy of Human Horizontal and Vertical Navigation in Real Space: Behavioral and PET Correlates.

Spatial orientation was tested during a horizontal and vertical real navigation task in humans. Video tracking of eye movements was used to analyse the behavioral strategy and combined with simultaneous measurements of brain activation and metabolism ([18F]-FDG-PET). Spatial navigation performance was significantly better during horizontal navigation. Horizontal navigation was predominantly visually and landmark-guided. PET measurements indicated that glucose metabolism increased in the right hippocampus, bilateral retrosplenial cortex, and pontine tegmentum during horizontal navigation. In contrast, vertical navigation was less reliant on visual and landmark information. In PET, vertical navigation activated the bilateral hippocampus and insula. Direct comparison revealed a relative activation in the pontine tegmentum and visual cortical areas during horizontal navigation and in the flocculus, insula, and anterior cingulate cortex during vertical navigation. In conclusion, these data indicate a functional anisotropy of human 3D-navigation in favor of the horizontal plane. There are common brain areas for both forms of navigation (hippocampus) as well as unique areas such as the retrosplenial cortex, visual cortex (horizontal navigation), flocculus, and vestibular multisensory cortex (vertical navigation). Visually guided landmark recognition seems to be more important for horizontal navigation, while distance estimation based on vestibular input might be more relevant for vertical navigation.

Regio- and Enantioselective Synthesis of Azole Hemiaminal Esters by Lewis Base Catalyzed Dynamic Kinetic Resolution.

We report a modular three-component dynamic kinetic resolution (DKR) that affords enantiomerically enriched hemiaminal esters derived from azoles and aldehydes. The novel and scalable reaction can be used to synthesize valuable substituted azoles in a regioselective manner by capping (e.g., acylation) of the equilibrating azole-aldehyde adduct. With the use of a prolinol-derived DMAP catalyst as the chiral Lewis base, the products can be obtained in high chemical yield and with high enantiomeric excess. The DKR was performed on a multikilogram scale to produce a tetrazole prodrug fragment for a leading clinical candidate that posed formidable synthesis challenges.

Latent herpes simplex virus 1 infection does not induce apoptosis in human trigeminal Ganglia.

Herpes simplex virus 1 (HSV-1) can establish lifelong latency in human trigeminal ganglia. Latently infected ganglia contain CD8(+) T cells, which secrete granzyme B and are thus capable of inducing neuronal apoptosis. Using immunohistochemistry and single-cell reverse transcription-quantitative PCR (RT-qPCR), higher frequency and transcript levels of caspase-3 were found in HSV-1-negative compared to HSV-1-positive ganglia and neurons, respectively. No terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay-positive neurons were detected. The infiltrating T cells do not induce apoptosis in latently infected neurons.