New Constraint on the Local Relic Neutrino Background Overdensity with the First KATRIN Data Runs.

We report on the direct search for cosmic relic neutrinos using data acquired during the first two science campaigns of the KATRIN experiment in 2019. Beta-decay electrons from a high-purity molecular tritium gas source are analyzed by a high-resolution MAC-E filter around the end point at 18.57 keV. The analysis is sensitive to a local relic neutrino overdensity ratio of η<9.7×10^{10}/α (1.1×10^{11}/α) at a 90% (95%) confidence level with α=1 (0.5) for Majorana (Dirac) neutrinos. A fit of the integrated electron spectrum over a narrow interval around the end point accounting for relic neutrino captures in the tritium source reveals no significant overdensity. This work improves the results obtained by the previous neutrino mass experiments at Los Alamos and Troitsk. We furthermore update the projected final sensitivity of the KATRIN experiment to η<1×10^{10}/α at 90% confidence level, by relying on updated operational conditions.

Bound on 3+1 Active-Sterile Neutrino Mixing from the First Four-Week Science Run of KATRIN.

We report on the light sterile neutrino search from the first four-week science run of the KATRIN experiment in 2019. Beta-decay electrons from a high-purity gaseous molecular tritium source are analyzed by a high-resolution MAC-E filter down to 40 eV below the endpoint at 18.57 keV. We consider the framework with three active neutrinos and one sterile neutrino. The analysis is sensitive to the mass, m_{4}, of the fourth mass state for m_{4}^{2}≲1000 eV^{2} and to active-to-sterile neutrino mixing down to |U_{e4}|^{2}≳2×10^{-2}. No significant spectral distortion is observed and exclusion bounds on the sterile mass and mixing are reported. These new limits supersede the Mainz results for m_{4}^{2}≲1000 eV^{2} and improve the Troitsk bound for m_{4}^{2}<30 eV^{2}. The reactor and gallium anomalies are constrained for 100<Δm_{41}^{2}<1000 eV^{2}.

Improved Upper Limit on the Neutrino Mass from a Direct Kinematic Method by KATRIN.

We report on the neutrino mass measurement result from the first four-week science run of the Karlsruhe Tritium Neutrino experiment KATRIN in spring 2019. Beta-decay electrons from a high-purity gaseous molecular tritium source are energy analyzed by a high-resolution MAC-E filter. A fit of the integrated electron spectrum over a narrow interval around the kinematic end point at 18.57 keV gives an effective neutrino mass square value of (-1.0_{-1.1}^{+0.9}) eV^{2}. From this, we derive an upper limit of 1.1 eV (90% confidence level) on the absolute mass scale of neutrinos. This value coincides with the KATRIN sensitivity. It improves upon previous mass limits from kinematic measurements by almost a factor of 2 and provides model-independent input to cosmological studies of structure formation.

[Drug-induced seizures]. / Medikamentös induzierte epileptische Anfälle.

Drug-induced seizures are in view of a constantly ageing population and increasingly frequent polypharmacotherapy an increasing problem in daily routine praxis. Identification of potentially seizure-inducing drugs may help generating risk profiles for individual patients. Drug-induced seizures have often been seen as a complication of psychopharmacological therapy, but its occurrence has also been described in response to a great diversity of compounds such as antibiotics, sympathomimetics and anaesthetics. The present article outlines a synopsis of the most prevalent seizure-inducing drugs as well as strategies how to deal with a patient suffering from a drug-induced seizure.

[Zerebrale Amyloidangiopathie : Cerebral amyloid angiopathy]. / Zerebrale Amyloidangiopathie : Cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is defined by the accumulation of ß-amyloid in the walls of cortical arteries. The risk factors of CAA include advanced age and the presence of certain alleles of apolipoprotein E. CAA mostly remains asymptomatic, but the classical manifestation is intracerebral hemorrhage. A definite diagnosis can only be made on the basis of histopathological examination. Detection of lobar hemorrhages and lobar microhemorrhages in imaging investigations support the diagnosis of CAA as long as other causes can be excluded.

[Drug-induced tremor]. / Medikamentös-induzierter Tremor.

Drug-induced tremor is an important differential diagnosis for tremor syndromes. In view of a constantly ageing population and increasingly frequent polypharmacotherapy, identification of potentially tremor-inducing drugs may help generating risk profiles for individual patients. Drug-induced tremor has often been seen as a complication of antipsychotic therapy, but its occurrence has also been described in response to a great diversity of compounds such as antidepressants, sympathomimetics, antiarrhythmics, antiepileptics and other drugs. The present article presents a synopsis of the most prevalent tremor-inducing drugs as well as strategies to overcome drug-induced tremor, either by replacement of the causative drug or by symptomatic therapies.

[Antiepileptic drug-induced encephalopathy]. / Antiepileptika-induzierte Enzephalopathie.

The clinical features of an antiepileptic drug-induced encephalopathy (ADE) are confusion, reduction of vigilance, neurological deficits or an increase of the seizure frequency. In the electroencephalogram a general slowing or epileptic discharges are found. Characteristic are non-toxic blood levels of the antiepileptic drugs. So far an ADE was reported under phenytoin, carbamazepine or valproatic acid (valproate) therapy. More seldom, an ADE has been described after the intake of vigabatrine, lamotrigine und topiramate. Potential pathogenic mechanisms of AED are hyperammonemia, intrinsic effects on cerebral receptors, drug interactions, hepatic enzyme interactions, metabolic reasons or paradoxical proconvulsive effects of antiepileptic drugs. The medicamentous therapy consists of an immediate discontinuation of the antiepileptic drug.

Inflammation in areas of remote changes following focal brain lesion.

Focal brain lesions can lead to metabolic and structural changes in areas distant from but connected to the lesion site. After focal ischemic or excitotoxic lesions of the cortex and/or striatum, secondary changes have been observed in the thalamus, substantia nigra pars reticulata, hippocampus and spinal cord. In all these regions, inflammatory changes characterized by activation of microglia and astrocytes appear. In the thalamus, substantia nigra pars reticulata and hippocampus, an expression of proinflammatory cytokine like tumor necrosis factor-alpha and interleukin-1beta is induced. However, time course of expression and cellular localisation differ between these regions. Neuronal damage has consistently been observed in the thalamus, substantia nigra and spinal cord. It can be present in the hippocampus depending on the procedure of induction of focal cerebral ischemia. This secondary neuronal damage has been linked to antero- and retrograde degeneration. Anterograde degeneration is associated with somewhat later expression of cytokines, which is localised in neurons. In case of retrograde degeneration, the expression of cytokines is earlier and is localised in astrocytes. Pharmacological intervention aiming at reducing expression of tumor necrosis factor-alpha leads to reduction of secondary neuronal damage. These first results suggest that the inflammatory changes in remote areas might be involved in the pathogenesis of secondary neuronal damage.

Global ischemia and behavioural deficits.

Global cerebral ischemia in rodents is an established model in experimental research on cerebral ischemia which is characterized morphologically by a selective neuronal damage in the hippocampus, striatum and cortex. Using this model many studies have been performed to examine the pathophysiology of ischemic neuronal damage. Based upon these results it has been analysed whether substances which interact with the pathophysiological processes reduce the ischemic neuronal damage. Besides the morphological changes global ischemia leads to functional changes which can be assessed by behavioural studies. The Morris water maze examines the animals' abilities to learn, remember and go to a place in space only defined by its position relative to distal extramaze cues. In this test ischemic animals display a deficit in spatial learning as revealed by an increase in latency and in swim distance in the escape trials and a deficit in spatial memory as shown by reduced quadrant time and crossings over the former platform position during the probe trial. In several studies it could be demonstrated that neuroprotective strategies which reduce ischemic neuronal damage also attenuate or even completely prevent the ischemia-induced behavioural deficits in the water maze. Transplantation of fetal tissue which can also be used to achieve morphological recovery following global ischemia results in an amelioration of the ischemia-induced deficit. Thus, the water maze can clearly show that transplanted tissue can be functionally relevant. Data from the water maze seem to be a valuable completion to morphology which is especially important with respect to the relevance of experimental studies for clinical trials.

[Neurological diseases and pregnancy: what must the family physician heed?]. / Neurologische Erkrankungen in der Schwangerschaft. Welche Untersuchung und welche Therapie istjetzt noch erlaubt?

A woman in child-bearing age could principally contract a neurological disease during a pregnancy. The diseases are differentiated between those that existed before, such as migraines, epilepsy, multiple sclerosis or myasthenia gravis and diseases that have an increased incidence during pregnancy, for example stroke, thrombosis of a sinus, subarachnoid hemorrhage, restless legs syndrome or thoracic outlet syndromes and pregnancy specific diseases. The diagnostics and therapy of these diseases are limited by the pregnancy; contraindications must be observed.

Syntheses, analgetic activity, and physical dependence capacity of 5-phenyl-6,7-benzomorphan derivatives.

The synthesis, analgetic activity, and physical dependence capacity of a large number of 5-phenyl-6,7-benzomorphan derivatives are described. Observations made during the Stevens' rearrangement of 1-benzyl-1-methyl-delta 3-piperidinium salt derivatives (V) under various conditions are discussed. The absolute configuration of the 9-demethyl series and the 2'-deoxy series is established by comparison of their ORD and CD spectra with those of 49, whose absolute configuration was previously established by X-ray crystallography. A convenient synthesis of 3H-labeled phenols using 3H3PO4 is described, as well as the preparation of 14C-labeled compounds by conventional methods.

Expression of interleukin 6 in the rat striatum following stereotaxic injection of quinolinic acid.

Stereotaxic intrastriatal injection of the naturally occurring N-methyl-D-aspartate (NMDA) agonist quinolinic acid (QA) serves as a valuable in vivo model to study excitotoxic cell damage in the central nervous system (CNS). Although morphological changes such as neuronal loss, glial activation and remote reactions following QA injection have been described in some detail, much less is known about the molecular mechanisms mediating the accompanying glial response. Cytokines are known to play a crucial role in almost all kinds of CNS alterations. We now demonstrate that IL-6, a multifunctional glycoprotein which belongs to the family of neurokines, is expressed endogenously in the rat striatum following QA injection. Using Northern blot analysis, a massive but transient upregulation of IL-6 mRNA could be detected. This started 3 h after QA injection, reached a maximum at 6 h and disappeared within 24 h. That activated microglia are the most likely cellular source of the observed corresponding IL-6 protein expression could be concluded by comparing the immunocytochemical pattern of IL-6 expression and microglial activation. Interestingly, astrocytes initially downregulate their expression of glial fibrillary acidic protein (GFAP) in the excitotoxically injured striatum, but show a delayed increase in GFAP immunoreactivity starting in the periphery of the striatum, subsequently expanding to the core. The early transient IL-6 expression may play an important role in initiating the delayed astrocytic response following excitotoxic cell injury.

Global ischemic neuronal damage relates to behavioural deficits: a pharmacological approach.

Global cerebral ischemia leads morphologically to selective neuronal damage in the CA1 sector of the hippocampus and in the striatum and functionally to a deficit in spatial learning and memory in the water maze. The results of earlier studies which examined the relationship between neuronal damage and the deficits in the water maze were not clear cut. It has been observed, however, that neuroprotection reduces both the deficits in the water maze as well as the neuronal damage. The present study therefore approached the relationship between the neuronal damage and the deficits in water maze using pharmacological means. Global cerebral ischemia was induced in male Wistar rats by four-vessel occlusion for 20 min. Ischemic rats were treated with the N-methyl-D-aspartate receptor antagonist dextromethorphan, 50 mg/kg, with the calcium antagonist levemopamil, 30 mg/kg, with the radical scavenger EPC-K1, 10 mg/kg, or with solvent. Treatment with dextromethorphan or levemopamil reduced the deficit in spatial learning by limiting the increase in swim distance due to ischemia. Both substances also reduced the deficit in spatial memory by minimizing the ischemia-induced reduction in time spent in the quadrant of the former platform position during the probe trial. EPC-K1 had no influence on the ischemia-induced behavioural changes. Group comparisons demonstrated that the swim speed and the percentage of the swimming path along the sidewall were affected neither by ischemia nor by any of the treatments. Histological examination revealed neuronal damage in the hippocampus and in the striatum in all of the ischemic rats. Treatment with dextromethorphan or levemopamil reduced the hippocampal damage by 32% and 36%, respectively. In addition, dextromethorphan diminished the striatal damage about 78%. Correlation analysis demonstrated a correlation between the cumulative swim distance of all 20 escape trials and hippocampal damage (r = 0.65, P < 0.001) but not between swim distance and striatal damage (r = 0.14, P = 0.364). No correlation was found between quadrant time of the probe trial and either hippocampal damage (r = -0.21, P = 0.19) or striatal damage (r = -0.02, P = 0.889). The average percentage of the swimming path along the side wall related to the hippocampal damage (r = 0.28, P = 0.035) but not to the striatal damage (r = 0.05, P = 0.381). With respect to the average swim speed a correlation to striatal damage was observed (r = -0.69, P < 0.001) but not to hippocampal damage (r = -0.15, P = 0.168). These results clearly demonstrate that using the pharmacological approach it is possible to uncover certain correlations between functional deficits in the water maze and neuronal damage which are both due to global cerebral ischemia.

Tumor necrosis factor-alpha expression in areas of remote degeneration following middle cerebral artery occlusion of the rat.

Remote areas undergoing delayed neuronal degeneration after focal brain ischemia display a preceding glial activation. The expression of proinflammatory cytokines there has not been examined so far. We examined the expression of TNFalpha in the thalamus and the substantia nigra pars reticulata (SNr) 1, 3 and 7 days after transient middle cerebral artery occlusion (MCAO) of the rat. We used antibodies against glial fibrillary acidic protein (GFAP), OX-42, NeuN and tumor necrosis factor-alpha (TNFalpha) for immunohistochemistry/double-immunofluorescent labeling to investigate the time course of glial activation and the cellular localization of TNFalpha. Neuronal degeneration was measured by means of cell counting in Nissl-stained sections. In the ipsilateral thalamus, TNFalpha was upregulated already 1 day after MCAO. Microglia and astroglia were activated after 3 days. A cellular colocalisation of GFAP and TNFalpha was observed. Neuronal degeneration was evident at day 14. In the SNr, TNFalpha expression was enhanced 3 days after MCAO. Microglia was activated after 3 days and astroglia after 7 days. A cellular colocalisation of NeuN and TNFalpha was observed. Neuronal degeneration was evident at day 14. Thus, in both areas, expression of TNFalpha precedes astrogliosis and neuronal degeneration. The different patterns of TNFalpha upregulation of the substantia nigra pars reticulata and the thalamus following middle cerebral artery occlusion may reflect different pathophysiological mechanisms leading to remote neuronal degeneration.

Altered pattern of immunohistochemical staining for glial fibrillary acidic protein (GFAP) in the forebrain and cerebellum of the mutant spastic rat.

The spastic rat is a neurological mutant of the Han-Wistar strain with prominent spasticity, tremor, and ataxia. Neurodegeneration is found in the CA3 sector of the hippocampus and in Purkinje cells of the cerebellum. We examined the forebrain and cerebellum of spastic rats for glial reactions by using immunolabelling for the astrocytic marker, glial fibrillary acidic protein (GFAP). First, a map of the GFAP-distribution was made representing a systematic series of frontal sections in controls. Reactive astrocytes with increased GFAP should occur in the areas with established neuronal degeneration, but they could also demarcate further regions with pathology in this rat strain. Since the baseline levels of GFAP-immunoreactivity differ between brain regions, control rats and clinically normal littermates served as controls to judge relative increases in major structures. In the CA3 sector and hilus of the dorsal hippocampus, a massive gliosis was detected. In the cerebellum, a patchy increase of GFAP labelling in Bergmann glia was found. Further increases of GFAP-labelling in reactive astrocytes occurred in fiber tracts, the ventral thalamic nuclei, medial geniculate nuclei, pontine region and optic layer of the superior colliculus. Inconsistent changes were noted in cortex and pallidum. No defects of glial labelling or malformations in glial architectonics were found. The reactive changes of astroglial cells in hippocampus and cerebellum are in proportion to the neuronal degeneration. The glial reactions in the other brain regions possibly reflect a reaction to fiber degeneration and incipient neuronal degeneration or functional alterations of glial cells in response to neuronal dysfunction.

N-methyl-D-aspartate (NMDA)-mediated muscle relaxant action of dextromethorphan in rats.

The present study examined whether the antitussive agent dextromethorphan, which is an antagonist at the N-methyl-D-aspartate (NMDA) receptor, depresses spinal reflexes in rats. Injection of both the specific NMDA antagonist (-)-2-amino-7-phosphonoheptanoate and of dextromethorphan dose-dependently reduced the magnitude of the polysynaptic flexor reflex without affecting the monosynaptic H-reflex. In contrast, the non-NMDA antagonist 6,7-dinitroquinoxaline-2,3-dione depressed the H-reflex in a dose-dependent manner without affecting the flexor reflex. The depressant effect of dextromethorphan on the flexor reflex was prevented by co-administration with NMDA but not with the non-NMDA agonist alpha-amino-3-hydroxy-5-terthyl-4-isoxazole-propionic acid. These data suggest that dextromethorphan exerts a muscle relaxant action via the NMDA receptor.

Expression of GFAP in the striatum and its projection areas in response to striatal quinolinic acid lesion in rats.

Injection of quinolinic acid (QA) into the rat striatum is known to produce neuropathological and neurochemical features of Huntington's disease (HD). In the present study the astrocytic response two weeks following intrastriatal injection of either QA (240 nmol) or solvent (1 microliter) was examined using immunohistochemistry for GFAP. Striatal QA lesion resulted in a marked GFAP expression within the whole striatum which is due to neuronal degeneration. Furthermore, the reticular part of substantia nigra, globus pallidus and ventromedial thalamic nucleus revealed increases in GFAP expression without neuronal damage. As this remote astrocytic response is located only in striatal projection areas it seems to reflect transsynaptic changes in response to the lesion.

N-methyl-D-aspartate (NMDA)-mediated muscle relaxant action of flupirtine in rats.

The present study examined in urethane-chloralose anaesthetized rats whether N-methyl-D-aspartate (NMDA) is involved in the depressant effect of flupirtine on the monosynaptic Hoffmann (H)-reflex recorded from plantar foot muscles and on polysynaptic flexor reflexes recorded from tibialis muscle. Intrathecal administration of both the specific NMDA antagonist (-)-2-amino-7-phosphonoheptanoate and of flupirtine depressed the polysynaptic flexor reflex without affecting the monosynaptic H-reflex. In contrast, the non-NMDA antagonist 6,7-dinitroquinoxaline-2,3-dione depressed the H-reflex without affecting the flexor reflex. The depressant effect of flupirtine on the flexor reflex was prevented by co-administration of NMDA, but not by co-administration of the non-NMDA agonist alpha-amino-3-hydroxy-5-tertbutyl-4-isoxazolepropionic acid. These observations suggest that NMDA might be involved in the action of flupirtine.