[Otorhinolaryngological diseases in pregnancy-which drugs are approved?] / HNO-ärztliche Krankheitsbilder in der Schwangerschaft ­ welche Medikamente sind zulässig?

Between 1958 and 1961 approximately 10,000 children with severe deformities of extremities were born, whose mothers had taken the sedative thalidomide. Since then, drugs in pregnancy are applied with legitimate caution by the pharmaceutical industry, physicians and patients, although often accompanied by irrational panic. The pharmaceutical industry takes a legally safe position noting "contraindication" or at least "strict indication" in the consumer information. This transfers responsibility to the prescribing doctor. Even without drug therapy, the spontaneous malformation rate is approx. 3 to 4%. Concerning expectant mothers, a therapeutic nihilism may lead to a dramatic deterioration of the maternal disease, thereby causing high risks in fetal development. The aim of the present work is to present a structured "Guideline for Practice" of medication that can be used during pregnancy for treating medical conditions of the ear, nose and throat.

Isometric agonist and antagonist muscle activation interacts differently with 140-Hz transcranial alternating current stimulation aftereffects at different intensities.

During transcranial electric stimulation, increasing intracellular Ca2+ levels beyond those needed for inducing long term potentiation (LTP) may collapse aftereffects. State-dependent plastic aftereffects are reduced when applied during muscle activation as compared with rest. Cortical surround inhibition by antagonistic muscle activation inhibits the center-innervated agonist. The objective of this study is to determine the interaction of state dependency of transcranial alternating current stimulation (tACS) aftereffects at rest and under activation of agonist and antagonist muscles during stimulation with different intensities. In 13 healthy participants, we measured motor-evoked potential (MEP) amplitudes before and after applying tACS at 140 Hz over the motor cortex in nine single-blinded sessions using sham, 1 mA, and 2 mA stimulation intensities during rest and activation of agonist and antagonist muscles. During rest, only 1 mA tACS produced a significant MEP increase, whereas the 2 mA stimulation produced no significant MEP size shift. During agonist activation 1 mA did not induce MEP changes; after 2 mA, first a decrease and later an increase of MEPs were observed. Antagonist activation under sham tACS led to an inhibition, which was restored to baseline by 1 and 2 mA tACS. Increasing stimulation intensity beyond 1 mA does not increase excitability, compatible with too strong intracellular Ca2+ increase. Antagonist innervation leads to MEP inhibition, supporting the concept of surround inhibition, which can be overcome by tACS at both intensities. During agonist innervation, a tACS dose-dependent relationship exists. Our results integrate concepts of "leaky membranes" under activation, surround inhibition, intracellular Ca2+ increase, and their role in the aftereffects of tACS.NEW & NOTEWORTHY Stimulation intensity and activation of center versus surround muscles affect cortical excitability alterations generated by 140-Hz tACS. At rest, excitatory aftereffects were induced by tACS with 1 mA, but not 2 mA stimulation intensity. With agonistic muscle activation, excitability first decreases, and then increases with 2 mA. For antagonist activation, the MEP amplitude reduction observed in the sham condition is counteracted upon by 1 and 2 mA tACS. This reflects the relation of LTP-like aftereffects to Ca2+ concentration alterations.

Sex influences the frequency of the posterior basic alpha rhythm in patients with epilepsy.

OBJECTIVE: To determine effects of sex, epilepsy and epilepsy medication on the posterior basic alpha rhythm. METHODS: We reviewed the routine EEGs of 160 subjects, including 60 individuals with focal epilepsy, 60 with generalized epilepsy, and 40 healthy controls, measured the mean alpha frequencies of each person and applied a univariate three-factorial analysis of variance. RESULTS: Women have a significantly faster posterior basic rhythm as compared to men. Sex was the only independent factor influencing the posterior basic rhythm in this cohort. Additionally, we detected an interaction with intake of lamotrigine and idiopathic generalized epilepsy both increasing the basic alpha frequency in the group of female subjects only. CONCLUSION: Sex was the main determinant of the posterior basic alpha frequency in our cohort. SIGNIFICANCE: Sex can influence the frequency of the posterior basic alpha rhythm.

Neuronal tuning: Selective targeting of neuronal populations via manipulation of pulse width and directionality.

INTRODUCTION: Motor evoked potentials (MEP) in response to anteroposterior transcranial (AP) magnetic stimulation (TMS) are sensitive to the TMS pulse shape. We are now able to isolate distinct pulse properties, such as pulse width and directionality and evaluate them individually. Different pulse shapes induce different effects, likely by stimulating different populations of neurons. This implies that not all neurons respond in the same manner to stimulation, possibly, because individual segments of neurons differ in their membrane properties. OBJECTIVES: To investigate the effect of different pulse widths and directionalities of TMS on MEP latencies, motor thresholds and plastic aftereffects of rTMS. METHODS: Using a controllable pulse stimulator TMS (cTMS), we stimulated fifteen subjects with quasi-unidirectional TMS pulses of different pulse durations (40 µs, 80 µs and 120 µs) and determined thresholds and MEP AP latencies. We then compared the effects of 80 µs quasi-unidirectional pulses to those of 80 µs pulses with different pulse directionality characteristics (0.6 and 1.0 M ratios). We applied 900 pulses of the selected pulse shapes at 1 Hz. RESULTS: The aftereffects of 1 Hz rTMS depended on pulse shape and duration. 40 and 80 µs wide unidirectional pulses induced inhibition, 120 µs wide pulses caused excitation. Bidirectional pulses induced inhibition during the stimulation but had facilitatory aftereffects. Narrower pulse shapes caused longer latencies and higher resting motor thresholds (RMT) as compared to wider pulse shapes. CONCLUSIONS: We can tune the aftereffects of rTMS by manipulating pulse width and directionality; this may be due to the different membrane properties of the various neuronal segments such as dendrites. SIGNIFICANCE: To date, rTMS frequency has been the main determinant of the plastic aftereffects. However, we showed that pulse width also plays a major role, probably by recruiting novel neuronal targets.

[Frequent neurological diseases associated with the restless legs syndrome]. / Häufige neurologische Erkrankungen assoziiert mit dem Restless-legs-Syndrom.

BACKGROUND: Restless legs syndrome (RLS) is a common neurological disease. Studies have shown that RLS is associated with a variety of medical and neurological disorders. OBJECTIVES: Using the example of three associated neurological diseases, the significance for everyday therapy decisions is assessed. MATERIAL AND METHODS: A systematic search was carried out in PubMed for all studies with the keyword "RLS" in combination with polyneuropathies (PNP), Parkinson's disease (PD) and multiple sclerosis (MS) and classified according to the methodology in high, medium or low study quality. RESULTS: Of 16 studies on RLS and MS, 10 were rated as "high". The high association frequency of RLS in MS between 13.3% and 65.1% (the variability possibly originates from different methods) prevents further statements about the prevalence. Within 30 studies on Parkinson's disease 17 were classified as having a high quality. In patients with Parkinson disease RLS occurs most frequently during therapy and is related to the duration of dopaminergic treatment. In patients with polyneuropathy, only 5 out of 24 studies were classified as being of high quality and an increased RLS prevalence was detected for acquired polyneuropathies with heterogeneous data for hereditary forms. CONCLUSION: There is an increased prevalence of association with RLS for the diseases discussed. This prevalence is possibly determined by the pathophysiology of these disorders. These diseases are possibly characterized by genetic predispositions as well, which can hopefully be classified more accurately in the future.

Decreased cerebral Irp-1B limits impact of social isolation in wild type and Alzheimer's disease modeled in Drosophila melanogaster.

Environmental factors, such as housing conditions and cognitively stimulating activities, have been shown to affect behavioral phenotypes and to modulate neurodegenerative conditions such as Alzheimer's disease (AD). AD is a progressive neurodegenerative disorder affecting cognitive functions. Epidemiological evidence and experimental studies using rodent models have indicated that social interaction reduces development and progression of disease. Drosophila models of Aß42-associated AD lead to AD-like phenotypes, such as long-term memory impairment, locomotor and survival deficits, while effects of environmental conditions on AD-associated phenotypes have not been assessed in the fly. Here, we show that single housing reduced survival and motor performance of Aß42 expressing and control flies. Gene expression analyses of Aß42 expressing and control flies that had been exposed to different housing conditions showed upregulation of Iron regulatory protein 1B (Irp-1B) in fly brains following single housing. Downregulating Irp-1B in neurons of single-housed Aß42 expressing and control flies rescued both survival and motor performance deficits. Thus, we provide novel evidence that increased cerebral expression of Irp-1B may underlie worsened behavioral outcome in socially deprived flies and can additionally modulate AD-like phenotypes.

Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines.

Low intensity transcranial electrical stimulation (TES) in humans, encompassing transcranial direct current (tDCS), transcutaneous spinal Direct Current Stimulation (tsDCS), transcranial alternating current (tACS), and transcranial random noise (tRNS) stimulation or their combinations, appears to be safe. No serious adverse events (SAEs) have been reported so far in over 18,000 sessions administered to healthy subjects, neurological and psychiatric patients, as summarized here. Moderate adverse events (AEs), as defined by the necessity to intervene, are rare, and include skin burns with tDCS due to suboptimal electrode-skin contact. Very rarely mania or hypomania was induced in patients with depression (11 documented cases), yet a causal relationship is difficult to prove because of the low incidence rate and limited numbers of subjects in controlled trials. Mild AEs (MAEs) include headache and fatigue following stimulation as well as prickling and burning sensations occurring during tDCS at peak-to-baseline intensities of 1-2mA and during tACS at higher peak-to-peak intensities above 2mA. The prevalence of published AEs is different in studies specifically assessing AEs vs. those not assessing them, being higher in the former. AEs are frequently reported by individuals receiving placebo stimulation. The profile of AEs in terms of frequency, magnitude and type is comparable in healthy and clinical populations, and this is also the case for more vulnerable populations, such as children, elderly persons, or pregnant women. Combined interventions (e.g., co-application of drugs, electrophysiological measurements, neuroimaging) were not associated with further safety issues. Safety is established for low-intensity 'conventional' TES defined as <4mA, up to 60min duration per day. Animal studies and modeling evidence indicate that brain injury could occur at predicted current densities in the brain of 6.3-13A/m2 that are over an order of magnitude above those produced by tDCS in humans. Using AC stimulation fewer AEs were reported compared to DC. In specific paradigms with amplitudes of up to 10mA, frequencies in the kHz range appear to be safe. In this paper we provide structured interviews and recommend their use in future controlled studies, in particular when trying to extend the parameters applied. We also discuss recent regulatory issues, reporting practices and ethical issues. These recommendations achieved consensus in a meeting, which took place in Göttingen, Germany, on September 6-7, 2016 and were refined thereafter by email correspondence.

Diverging effects of nicotine on motor learning performance: Improvement in deprived smokers and attenuation in non-smokers.

Nicotine modulates cognition and neuroplasticity in smokers and non-smokers. A possible mechanism for its effect on learning and memory performance is its impact on long-term potentiation (LTP) and long-term depression (LTD). As neuroplasticity is closely connected to learning processes, we aimed to explore the effect of nicotine in healthy, young smokers and non-smokers on performance of the serial reaction time task (SRTT), a sequential motor learning paradigm. 20 nicotine-deprived smokers and 20 non-smokers participated in the study and were exposed to nicotine or placebo medication. Deprived smokers under placebo medication displayed reduced performance in terms of reaction time and error rates compared to the non-smoking group. After application of nicotine, performance in smokers improved while it deteriorated in non-smokers. These results indicate a restituting effect of nicotine in smokers in terms of cognitive parameters. This sheds further light on the proposed mechanism of nicotine on learning processes, which might be linked to the addictive component of nicotine, the probability of relapse and thus needs also be addressed in cessation treatment.

Compromised neuroplasticity in cigarette smokers under nicotine withdrawal is restituted by the nicotinic α4ß2-receptor partial agonist varenicline.

Nicotine modulates neuroplasticity and improves cognitive functions in animals and humans. In the brain of smoking individuals, calcium-dependent plasticity induced by non-invasive brain stimulation methods such as transcranial direct current stimulation (tDCS) and paired associative stimulation (PAS) is impaired by nicotine withdrawal, but partially re-established after nicotine re-administration. In order to investigate the underlying mechanism further, we tested the impact of the α4ß2-nicotinic receptor partial agonist varenicline on focal and non-focal plasticity in smokers during nicotine withdrawal, induced by PAS and tDCS, respectively. We administered low (0.3 mg) and high (1.0 mg) single doses of varenicline or placebo medication before stimulation over the left motor cortex of 20 healthy smokers under nicotine withdrawal. Motor cortex excitability was monitored by single-pulse transcranial magnetic stimulation-induced motor evoked potential amplitudes for 36 hours after plasticity induction. Stimulation-induced plasticity was absent under placebo medication, whereas it was present in all conditions under high dose. Low dose restituted only tDCS-induced non-focal plasticity, producing no significant impact on focal plasticity. High dose varenicline also prolonged inhibitory plasticity. These results are comparable to the impact of nicotine on withdrawal-related impaired plasticity in smokers and suggest that α4ß2 nicotinic receptors are relevantly involved in plasticity deficits and restitution in smokers.

rTMS affects working memory performance, brain activation and functional connectivity in patients with multiple sclerosis.

OBJECTIVE: To investigate the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) of the right dorsolateral prefrontal cortex (DLPFC) on working memory performance, while measuring task-related brain activation and task-related brain connectivity in patients with multiple sclerosis (MS). METHODS: 17 patients with MS and 11 healthy controls (HCs) underwent 3 experimental sessions (baseline, real-rTMS, sham-rTMS), all including an N-back task (3 task loads: N1, N2, N3; control condition: N0) inside the MR scanner. Prior to imaging, real-rTMS (10 Hz) was applied to the right DLPFC. The stimulation site was defined based on individually assessed N-back task activation at baseline and located using neuronavigation. Changes in whole brain functional activation and functional connectivity with the right DLPFC were calculated. RESULTS: N-back task accuracy (N2 and N3) improved after real-rTMS (and not after sham-rTMS) compared with baseline (p=0.029 and p=0.015, respectively), only in patients. At baseline, patients with MS, compared with HCs, showed higher task-related frontal activation (left DLPFC, N2>N0), which disappeared after real-rTMS. Task-related (N1>N0) functional connectivity between the right DLPFC and the right caudate nucleus and bilateral (para)cingulate gyrus increased in patients after real-rTMS when compared with sham stimulation. CONCLUSIONS: In patients with MS, N-back accuracy improved while frontal hyperactivation (seen at baseline relative to HCs) disappeared after real-rTMS. Together with the changes in functional connectivity after real-rTMS in patients, these findings may represent an rTMS-induced change in network efficiency in patients with MS, shifting patients' brain function towards the healthy situation. This implicates a potentially relevant role for rTMS in cognitive rehabilitation in MS.

EAN guidelines on central neurostimulation therapy in chronic pain conditions.

BACKGROUND AND PURPOSE: Our aim was to update previous European Federation of Neurological Societies guidelines on neurostimulation for neuropathic pain, expanding the search to new techniques and to chronic pain conditions other than neuropathic pain, and assessing the evidence with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. METHODS: A systematic review and meta-analysis of trials published between 2006 and December 2014 was conducted. Pain conditions included neuropathic pain, fibromyalgia, complex regional pain syndrome (CRPS) type I and post-surgical chronic back and leg pain (CBLP). Spinal cord stimulation (SCS), deep brain stimulation (DBS), epidural motor cortex stimulation (MCS), repetitive transcranial magnetic stimulation (rTMS) and transcranial direct electrical stimulation (tDCS) of the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) were assessed. The GRADE system was used to assess quality of evidence and propose recommendations. RESULTS: The following recommendations were reached: 'weak' for SCS added to conventional medical management in diabetic painful neuropathy, CBLP and CRPS, for SCS versus reoperation in CBLP, for MCS in neuropathic pain, for rTMS of M1 in neuropathic pain and fibromyalgia and for tDCS of M1 in neuropathic pain; 'inconclusive' for DBS in neuropathic pain, rTMS and tDCS of the DLPFC, and for motor cortex tDCS in fibromyalgia and spinal cord injury pain. CONCLUSIONS: Given the poor to moderate quality of evidence identified by this review, future large-scale multicentre studies of non-invasive and invasive neurostimulation are encouraged. The collection of higher quality evidence of the predictive factors for the efficacy of these techniques, such as the duration, quality and severity of pain, is also recommended.

[Affective disorders during pregnancy : Therapy with antidepressants and mood stabilizers]. / Affektive Störungen in der Schwangerschaft : Therapie mit Antidepressiva und Mood Stabilizern.

BACKGROUND: It is not rare that the first manifestation or relapse of an affective disorder occurs during pregnancy. Should a pharmacological treatment be indicated, the selection of a suitable substance should be made on a basis which is as safe as possible. Even when treating women of childbearing age it should be assured that the psychotropic drug selected is safe to use during pregnancy as a high percentage of pregnancies are unplanned. OBJECTIVE: When assessing the risks and benefits of psychopharmacotherapy in women who are or wish to get pregnant, not only the exposure of the child to potentially teratogenic drug effects but also potential complications during or after pregnancy and long-term neuropsychological issues need to be addressed. METHODS: This article provides an overview of the currently available literature on the use of antidepressants and mood stabilizers during pregnancy. RESULTS: A growing body of increasingly reliable data for many antidepressants and mood stabilizers are available, which allow a good prediction of their suitability for use during pregnancy and lactation. CONCLUSION: When treating affective disorders during pregnancy an individual assessment of the benefits and risks for mother and child is required. The benefit of an appropriate treatment for the mother by including medication which may be potentially harmful to the child versus the risk of an insufficient treatment for the mother by excluding medication which may be potentially harmful to both the mother and the child need to be weighed up. When a suitable psychopharmacotherapy during pregnancy has been selected, the risk for mother and child can be minimized by incorporation of therapeutic drug monitoring.

[Psychopharmacotherapy during pregnancy : Which antipsychotics, tranquilizers and hypnotics are suitable?]. / Psychopharmakotherapie in der Schwangerschaft : Welche Antipsychotika, Tranquilizer und Hypnotika sind geeignet?

BACKGROUND: When administering psychotropic drugs during pregnancy not only the potential teratogenic effects on the child must be addressed but also the fetotoxic implications for pregnancy and/or the peripartum phase as well as possible neurocognitive developmental disorders must be considered. OBJECTIVE: Evaluation of the risks and benefits of administering psychotropic drugs during pregnancy or for women who wish to become pregnant. METHODS: The literature has been reviewed with the purpose of providing information on psychotropic drugs which can safely be administered during pregnancy. The review considers antipsychotics as well as tranquilizers and hypnotics. RESULTS: Data are available for a multitude of psychotropic drugs that allow a safe estimation on their suitability for use during pregnancy. CONCLUSION: When treating mental illnesses during pregnancy the option of administering drugs must not principally be ruled out. What is required is an individual assessment of benefits and risks. The risk of an untreated mental illness versus the benefit of a suitable treatment, which may include the use of medication and the potential harm to the infant must be evaluated. If certain rules are observed and a suitable drug is selected the risk to the newborn child and/or mother during pregnancy can be minimized. During pregnancy, therapeutic drug monitoring is indicated and increases the safety for use of drugs and preventing harm to both mother and infant.

Understanding heart failure with preserved ejection fraction: where are we today?

Heart failure with preserved ejection fraction (HFpEF) represents a complex and heterogeneous clinical syndrome, which is increasingly prevalent and associated with poor outcome. In contrast to heart failure with reduced ejection fraction (HFrEF), modern heart failure pharmacotherapy did not improve outcome in HFpEF, which was attributed to incomplete understanding of HFpEF pathophysiology, patient heterogeneity and lack of insight into primary pathophysiological processes. HFpEF patients are frequently elderly females and patients demonstrate a high prevalence of non-cardiac comorbidities, which independently adversely affect myocardial structural and functional remodelling. Furthermore, although diastolic left ventricular dysfunction represents the dominant abnormality in HFpEF, numerous ancillary mechanisms are frequently present, which also negatively impact on cardiovascular reserve. Over the past decade, clinical and translational research has improved insight into HFpEF pathophysiology and the importance of comorbidities and patient heterogeneity. Recently, a new paradigm for HFpEF was proposed, which states that comorbidities drive myocardial dysfunction and remodelling in HFpEF through coronary microvascular inflammation. Regarding the conceptual framework of HFpEF treatment, emphasis may need to shift from a 'one fits all' strategy to an individualised approach based on phenotypic patient characterisation and diagnostic and pathophysiological stratification of myocardial disease processes. This review will describe these novel insights from a pathophysiological standpoint.

Proteomic analysis of the plasma membrane-movement tubule complex of cowpea mosaic virus.

Cowpea mosaic virus forms tubules constructed from the movement protein (MP) in plasmodesmata (PD) to achieve cell-to-cell movement of its virions. Similar tubules, delineated by the plasma membrane (PM), are formed protruding from the surface of infected protoplasts. These PM-tubule complexes were isolated from protoplasts by immunoprecipitation and analysed for their protein content by tandem mass spectrometry to identify host proteins with affinity for the movement tubule. Seven host proteins were abundantly present in the PM-tubule complex, including molecular chaperonins and an AAA protein. Members of both protein families have been implicated in establishment of systemic infection. The potential role of these proteins in tubule-guided cell-cell transport is discussed.