[Hearing classification in patients with vestibular schwannoma using German-language test procedures]. / Hörklassen bei Patienten mit Vestibularisschwannom bei Verwendung deutschsprachiger Testverfahren.

BACKGROUND: Hearing function in patients with vestibular schwannoma is often classified according to the Gardner and Robertson (1988) or the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS, 1995) systems. These classification systems are based on English-language test procedures, there is no German-language equivalent. The aim of the study was to investigate the influence of various target parameters on hearing classification and to derive a recommendation for the use of German-language test methods. MATERIALS AND METHODS: The rules for speech audiometry based on English-language test procedures were applied to German speech test materials. In 91 patients with vestibular schwannoma, pure tone hearing thresholds, speech recognition thresholds, and speech discrimination at different sound pressure levels were measured. The patients were categorized according to the Gardner and Robertson and AAO-HNS classifications. RESULTS: In both the Gardner-Robertson and the AAO-HNS classifications, the number of patients in the hearing classes with serviceable hearing function (measured as Pure Tone Average across three (3PTA) or four (4PTA) frequencies) was highest when using the 3PTA0,5;1;2 kHz condition, followed by 4PTA0,5;1;2;3 kHz, 4PTA0,5;1;2;4 kHz, and 4PTA0,5;1;2;"3"kHz. If maximum word recognition score (WRSmax) was used instead of word recognition 40 dB above the sensation level (WRS40SL), more patients were classified into the hearing classes with serviceable hearing function, irrespective of the mean pure tone hearing threshold. CONCLUSION: The Gardner-Robertson and AAO-HNS classifications can be used in German-speaking settings. The Freiburg monosyllabic test can be used to determine speech discrimination scores or maximum word recognition.

Edge-State Wave Functions from Momentum-Conserving Tunneling Spectroscopy.

We perform momentum-conserving tunneling spectroscopy using a GaAs cleaved-edge overgrowth quantum wire to investigate adjacent quantum Hall edge states. We use the lowest five wire modes with their distinct wave functions to probe each edge state and apply magnetic fields to modify the wave functions and their overlap. This reveals an intricate and rich tunneling conductance fan structure which is succinctly different for each of the wire modes. We self-consistently solve the Poisson-Schrödinger equations to simulate the spectroscopy, reproducing the striking fans in great detail, thus, confirming the calculations. Further, the model predicts hybridization between wire states and Landau levels, which is also confirmed experimentally. This establishes momentum-conserving tunneling spectroscopy as a powerful technique to probe edge state wave functions.

Pretreatment resistance mutations and treatment outcomes in adults living with HIV-1: a cohort study in urban Malawi.

BACKGROUND: Pre-treatment drug resistance (PDR) among antiretroviral drug-naïve people living with HIV (PLHIV) represents an important indicator for the risk of treatment failure and the spread of drug resistant HIV variants. We assessed the prevalence of PDR and treatment outcomes among adults living with HIV-1 in Lilongwe, Malawi. METHODS: We selected 200 participants at random from the Lighthouse Tenofovir Cohort Study (LighTen). Serum samples were drawn prior to treatment initiation in 2014 and 2015, frozen, and later analyzed for the presence of HIV-1 drug resistance mutations. Amplicons were sequenced and interpreted by Stanford HIVdb interpretation algorithm 8.4. We assessed treatment outcomes by evaluating clinical outcome and viral suppression at the end of the follow-up period in October 2019. RESULTS: PDR testing was successful in 197 of 200 samples. The overall NNRTI- PDR prevalence was 13.7% (27/197). The prevalence of intermediate or high level NNRTI- PDR was 11.2% (22/197). The most common mutation was K103N (5.6%, 11/197), followed by Y181C (3.6%, 7/197). In one case, we detected an NRTI resistance mutation (M184V), in combination with multiple NNRTI resistance mutations. All HIV-1 isolates analyzed were of subtype C. Of the 27 patients with NNRTI- PDR, 9 were still alive, on ART, and virally suppressed at the end of follow-up. CONCLUSION: The prevalence of NNRTI- PDR was above the critical level of 10% suggested by the Global Action Plan on HIV Drug Resistance. The distribution of drug resistance mutations was similar to that seen in previous studies from the region, and further supports the introduction of integrase inhibitors in first-line treatment in Malawi. Furthermore, our findings underline the need for continued PDR surveillance and pharmacovigilance in Sub-Saharan Africa.

The dopamine-related polymorphisms BDNF, COMT, DRD2, DRD3, and DRD4 are not linked with changes in CSF dopamine levels and frequency of HIV infection.

We showed previously that higher levels in CSF dopamine in HIV patients are associated with the presence of the dopamine transporter (DAT) 10/10-repeat allele which was also detected more frequently in HIV-infected individuals compared to uninfected subjects. In the current study, we investigated further whether other genetic dopamine (DA)-related polymorphisms may be related with changes in CSF DA levels and frequency of HIV infection in HIV-infected subjects. Specifically, we studied genetic polymorphisms of brain-derived neurotrophic factor, catechol-O-methyltransferase, and dopamine receptors DRD2, DRD3, and DRD4 genetic polymorphisms in uninfected and HIV-infected people in two different ethnical groups, a German cohort (Caucasian, 72 individuals with HIV infection and 22 individuals without HIV infection) and a South African cohort (Xhosan, 54 individuals with HIV infection and 19 individuals without HIV infection). We correlated the polymorphisms with CSF DA levels, HIV dementia score, CD4+ T cell counts, and HIV viral load. None of the investigated DA-related polymorphisms was associated with altered CSF DA levels, CD4+ T cell count, viral load, and HIV dementia score. The respective allele frequencies were equally distributed between HIV-infected patients and controls. Our findings do not show any influence of the studied genetic polymorphisms on CSF DA levels and HIV infection. This is in contrast to what we found previously for the DAT 3'UTR VNTR and highlights the specific role of the DAT VNTR in HIV infection and disease.

[Neuroprotective medication in vestibular schwannoma surgery]. / Medikamentöse Neuroprotektion in der Vestibularisschwannomchirurgie.

BACKGROUND: Except for glucocorticoids there is a lack of neuroprotective medication in neurosurgical interventions. OBJECTIVE: An overview of clinical trials investigating administration of the calcium antagonist nimodipine and hydroxyethyl starch (HES) in vestibular schwannoma (VS) surgery is given. Basic research is addressed and potential neuroprotective effect mechanisms are discussed, as are perspectives for application of the concept to other types of surgery with a risk postoperative impairment of nerve function. MATERIALS AND METHODS: A selective PubMed search was performed and all 10 clinical trials corresponding to the search criteria were included. RESULTS: Four trials with an intraoperative start of the medication showed a positive effect for the preservation of facial nerve function and hearing preservation. A pilot study showed superiority of prophylactic treatment over intraoperative application. There were no significant results in a prospective multicenter phase III trial. After 1 year, postoperative facial nerve preservation rates were excellent in both groups. However, the risk of hearing loss was twice as high in the control group. A combined analysis of the phase III trial with its pilot study showed significant results for better hearing preservation rates in the treatment group (probably by increasing the case load). CONCLUSION: Prophylactic nimodipine can be recommended in VS surgery in patients with good preoperative hearing. The effect mechanisms of nimodipine and modifications to prophylaxis should be clarified in basic research.

Intrinsic Metastabilities in the Charge Configuration of a Double Quantum Dot.

We report a thermally activated metastability in a GaAs double quantum dot exhibiting real-time charge switching in diamond shaped regions of the charge stability diagram. Accidental charge traps and sensor backaction are excluded as the origin of the switching. We present an extension of the canonical double dot theory based on an intrinsic, thermal electron exchange process through the reservoirs, giving excellent agreement with the experiment. The electron spin is randomized by the exchange process, thus facilitating fast, gate-controlled spin initialization. At the same time, this process sets an intrinsic upper limit to the spin relaxation time.

Isothiazolone emissions from building products.

Adding biocides to dispersion products is a well-known practice to control microbial deterioration. Isothiazolones are among the most commonly used preservatives, in particular a mixture of 2-methyl-2H-isothiazol-3-one (MIT) and 5-chloro-2-methyl-2H-isothiazol-3-one (CIT). In recent years, for health reasons, due to its strong sensitizing effect, CIT has been replaced by 1,2-benzisothiazol-3-one (BIT). Furthermore, numerous products are now available for interiors containing the fungicidal active substance 2-octyl-2H-isothiazol-3-one (OIT). So far nearly nothing is known of the emission behavior of BIT and OIT. An analytical method was developed for these two isothiazolones and interior products containing BIT respectively OIT have been investigated in an emission chamber and in test rooms. The chamber tests revealed maximum concentrations of 6.7 µg OIT/m3, 1.9 µg BIT/m3, and 187 µg MIT/m3. Concentrations obtained in the test rooms were at levels up to 1.4 µg OIT/m3 and 29 µg MIT/m3. A noticeable finding was the very slight subsidence of OIT and BIT levels over several weeks. While MIT outgassed quickly, OIT in particular showed low concentrations, but prolonged evaporation.

Possible evidence for helical nuclear spin order in GaAs quantum wires.

We present transport measurements of cleaved edge overgrowth GaAs quantum wires. The conductance of the first mode reaches 2e(2)/h at high temperatures T≳10 K, as expected. As T is lowered, the conductance is gradually reduced to 1e(2)/h, becoming T independent at T≲0.1 K, while the device cools far below 0.1 K. This behavior is seen in several wires, is independent of density, and not altered by moderate magnetic fields B. The conductance reduction by a factor of 2 suggests lifting of the electron spin degeneracy in the absence of B. Our results are consistent with theoretical predictions for helical nuclear magnetism in the Luttinger liquid regime.

Autoimmunity, dendritic cells and relevance for Parkinson's disease.

Innate and adaptive immune responses in neurodegenerative diseases have become recently a focus of research and discussions. Parkinson's disease (PD) is a neurodegenerative disorder without known etiopathogenesis. The past decade has generated evidence for an involvement of the immune system in PD pathogenesis. Both inflammatory and autoimmune mechanisms have been recognized and studies have emphasized the role of activated microglia and T-cell infiltration. In this short review, we focus on dendritic cells, on their role in initiation of autoimmune responses, we discuss aspects of neuroinflammation and autoimmunity in PD, and we report new evidence for the involvement of neuromelanin in these processes.

A-trains for intraoperative monitoring in patients with recurrent vestibular schwannoma.

BACKGROUND: Second surgery of recurrent vestibular schwannoma (VS) after previous surgery, stereotactic radiosurgery (SR) or fractionated radiotherapy (FR) carries an increased risk for deterioration of facial nerve function, e.g., due to adhesions, underlining the need for intraoperative monitoring. Facial "Atrain" EMG activity ("traintime") correlates with the degree of postoperative facial palsy. Studies investigating A-trains in VS patients with previous surgery, SR or FR are missing. We therefore investigated the value of A-train monitoring in patients undergoing second surgery for VS. METHOD: Intraoperative EMG data from patients who underwent second surgery for VS after previous surgery, SR and/or FR at our institution between 2006 and 2012 were retrospectively analyzed. Ten patients were selected (5 male): Seven had previous SR/RT and MS, three previous surgery only. Traintime values and distribution was compared to published thresholds and to 77 patients who underwent first surgery for VS during the same time period. RESULTS: A-trains were recorded early after opening of the dura, before facial nerve preparation. Mean traintime was 46.9 s (18.51 s ­ 80.82 s) in patients with previous SR/RT. In patients with previous MS only, traintime was 0.06 s, 0.99 s and 22.46 s. Compared to the literature, traintime was higher than expected in six patients (four with previous SR/RT, two without), respectively seven compared to the 77 patients with first surgery (5 SR/RT). Seven patients with previous SR/RT and none with previous surgery showed diffuse A-train distributions without significant percentages in single channels, compared to 60 of 77 patients with first surgery (p <0.02). CONCLUSIONS: Especially SR/RT, but also previous surgery seems to induce changes in the facial nerve leading to hyperexcitability and exceedingly high traintime values. Based on these findings, A-train monitoring in this specific patient group should be interpreted with caution.

Increased dopaminergic neurotransmission in therapy-naïve asymptomatic HIV patients is not associated with adaptive changes at the dopaminergic synapses.

Central dopaminergic (DA) systems are affected during human immunodeficiency virus (HIV) infection. So far, it is believed that they degenerate with progression of HIV disease because deterioration of DA systems is evident in advanced stages of infection. In this manuscript we found that (a) DA levels are increased and DA turnover is decreased in CSF of therapy-naïve HIV patients in asymptomatic infection, (b) DA increase does not modulate the availability of DA transporters and D2-receptors, (c) DA correlates inversely with CD4+ numbers in blood. These findings show activation of central DA systems without development of adaptive responses at DA synapses in asymptomatic HIV infection. It is probable that DA deterioration in advanced stages of HIV infection may derive from increased DA availability in early infection, resulting in DA neurotoxicity. Our findings provide a clue to the synergism between DA medication or drugs of abuse and HIV infection to exacerbate and accelerate HIV neuropsychiatric disease, a central issue in the neurobiology of HIV.

HIV-induced immune activation: pathogenesis and clinical relevance - summary of a workshop organized by the German AIDS Society (DAIG e.v.) and the ICH Hamburg, Hamburg, Germany, November 22, 2008.

This manuscript is communicated by the German AIDS Society (DAIG) (www.daignet.de). It summarizes a series of presentations and discussions during a workshop on immune activation due to HIV infection. The workshop was held on November 22nd 2008 in Hamburg, Germany. It was organized by the ICH Hamburg under the auspices of the German AIDS Society (DAIG e.V.).

Progress in Cooling Nanoelectronic Devices to Ultra-Low Temperatures.

Here we review recent progress in cooling micro-/nanoelectronic devices significantly below 10 mK. A number of groups worldwide are working to produce sub-millikelvin on-chip electron temperatures, motivated by the possibility of observing new physical effects and improving the performance of quantum technologies, sensors and metrological standards. The challenge is a longstanding one, with the lowest reported on-chip electron temperature having remained around 4 mK for more than 15 years. This is despite the fact that microkelvin temperatures have been accessible in bulk materials since the mid-twentieth century. In this review, we describe progress made in the last 5 years using new cooling techniques. Developments have been driven by improvements in the understanding of nanoscale physics, material properties and heat flow in electronic devices at ultralow temperatures and have involved collaboration between universities and institutes, physicists and engineers. We hope that this review will serve as a summary of the current state of the art and provide a roadmap for future developments. We focus on techniques that have shown, in experiment, the potential to reach sub-millikelvin electron temperatures. In particular, we focus on on-chip demagnetisation refrigeration. Multiple groups have used this technique to reach temperatures around 1 mK, with a current lowest temperature below 0.5 mK.

Evolution of the quantum Hall bulk spectrum into chiral edge states.

One of the most intriguing and fundamental properties of topological systems is the correspondence between the conducting edge states and the gapped bulk spectrum. Here, we use a GaAs cleaved edge quantum wire to perform momentum-resolved spectroscopy of the quantum Hall edge states in a tunnel-coupled 2D electron gas. This reveals the momentum and position of the edge states with unprecedented precision and shows the evolution from very low magnetic fields all the way to high fields where depopulation occurs. We present consistent analytical and numerical models, inferring the edge states from the well-known bulk spectrum, finding excellent agreement with the experiment-thus providing direct evidence for the bulk to edge correspondence. In addition, we observe various features beyond the single-particle picture, such as Fermi level pinning, exchange-enhanced spin splitting and signatures of edge-state reconstruction.

The therapeutic potential of siRNA in gene therapy of neurodegenerative disorders.

RNA interference using small inhibitory RNA (siRNA) has become a powerful tool to downregulate mRNA levels by cellular nucleases that become activated when a sequence homology between the siRNA and a respective mRNA molecule is detected. Therefore siRNA can be used to silence genes involved in the pathogenesis of various diseases associated with a known genetic background. As for many neurodegenerative disorders a causative therapy is unavailable, siRNA holds a promising option for the development of novel therapeutic strategies. Here we discuss different siRNA target strategies aiming for an allele-specific degradation of disease-inducing mRNA and we review the literature in the field of siRNA and its application in animal models of neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and spinocerebellar ataxia (SCA1).

Biostatistical analysis of gene microarrays reveals diverse expression clusters between macaque subspecies in brain SIV infection.

In this study we investigated differences in the gene expression profiling of the brains of rhesus macaques that were uninfected or infected with SIV in the asymptomatic stage or AIDS. The main aim was to use biostatistical methods to classify brain gene expression following SIV infection, without consideration of the biological significance of the individual genes. We also used data from animals treated with different pharmacological substances such as dopaminergic drugs, N-methyl-D-aspartate (NMDA) antagonists or antioxidants during the early stage of infection as these animals exhibited an accelerated or attenuated neuropsychiatric disease progression. We found macaque subspecies to be a more important factor for disease classification based on gene expression profiling than clinical symptoms or neuropathological findings. It is noteworthy that SIV-infected pharmacologically-treated. Chinese animals clustered near uninfected animals independent on the outcome of the treatment, whereas untreated SIV infected animals were clustered in a separate subtree. It is clear from this study that NeuroAIDS is a diverse disease entity and that SIV brain genes can be differentially regulated, depending on the disease type as well as changed dependent on the monkey subspecies.

Apoptosis inhibition in T cells triggers the expression of proinflammatory cytokines--implications for the CNS.

Stimulation of death receptors such as CD95 or TNF-R1 results in rapid onset of apoptosis. Here we show that inhibition of death receptor-induced apoptosis by the broad range caspase inhibitor ZVAD causes a switch from apoptotic to proinflammatory signaling. In previous studies we have reported that caspase inhibitors induce expression of various proinflammatory cytokines in CD95-stimulated primary T cells, such as TNF-alpha, IFN-gamma and GM-CSF. In this study we provide further evidence for the proinflammatory activity of CD95. Stimulation of CD95 by agonistic antibodies (7C11) resulted in expression of IL-2 in primary T cells, which was further enhanced when caspase activity was blocked by ZVAD. Moreover, CD95 triggered expression of IL-4 and IL-8 when caspase activity was inhibited, but not in the absence of ZVAD. Our findings are of significant importance for the CNS as changes in the cytokine pattern in the periphery affects the entry of various immune cells into the brain. Moreover, invading activated T cells can also directly influence the cytokine profile within the brain, triggering signaling cascades that eventually lead to neuronal cell death. The use of caspase inhibitors to prevent apoptotic cell death should be carefully evaluated in the management of systemic and CNS diseases.